ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.9672dup (p.Tyr3225fs)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000059.4(BRCA2):c.9672dup (p.Tyr3225fs)
Variation ID: 126217 Accession: VCV000126217.76
- Type and length
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Duplication, 1 bp
- Location
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Cytogenetic: 13q13.1 13: 32398184-32398185 (GRCh38) [ NCBI UCSC ] 13: 32972321-32972322 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2014 Apr 20, 2024 Sep 8, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000059.4:c.9672dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.Tyr3225fs frameshift NM_000059.3:c.9672dupA NC_000013.11:g.32398185dup NC_000013.10:g.32972322dup NG_012772.3:g.87706dup LRG_293:g.87706dup U43746.1:n.9900_9901insA - Protein change
- Y3225fs
- Other names
- 9900insA
- p.Tyr3225IlefsX30
- Canonical SPDI
- NC_000013.11:32398184:A:AA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18542 | 18699 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Jul 26, 2002 | RCV000009922.13 | |
Pathogenic (9) |
reviewed by expert panel
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Sep 8, 2016 | RCV000114151.19 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Oct 20, 2022 | RCV000130631.19 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2023 | RCV000197712.24 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Nov 10, 2023 | RCV000372727.21 | |
Pathogenic (1) |
no assertion criteria provided
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- | RCV001353641.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 20, 2023 | RCV003390793.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2023 | RCV003460795.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 08, 2016)
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reviewed by expert panel
Method: curation
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Accession: SCV000301407.2
First in ClinVar: Sep 24, 2016 Last updated: Sep 24, 2016 |
Comment:
Variant allele predicted to encode a truncated non-functional protein.
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Pathogenic
(Oct 10, 2014)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743528.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Pathogenic
(Sep 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000744792.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Pathogenic
(Feb 12, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695261.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
Comment:
Variant summary: BRCA2 c.9672dupA (p.Tyr3225IlefsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: BRCA2 c.9672dupA (p.Tyr3225IlefsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249832 control chromosomes (gnomAD and publication). c.9672dupA has been reported in the literature in multiple individuals affected with breast cancer and/or ovarian cancer (Couch_2015, Rebbeck_2018, BIC database). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters, including one expert panel (ENIGMA), (evaluation after 2014) cite the variant as pathogenic (n=10) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Nov 15, 2021)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581551.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Jun 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000889186.3
First in ClinVar: Dec 19, 2017 Last updated: Dec 31, 2022 |
Comment:
The BRCA2 c.9672dup (p.Tyr3225Ilefs*30) frameshift variant (also known as c.9672_9673insA and 9900insA) alters the translational reading frame of the BRCA2 mRNA and is predicted to … (more)
The BRCA2 c.9672dup (p.Tyr3225Ilefs*30) frameshift variant (also known as c.9672_9673insA and 9900insA) alters the translational reading frame of the BRCA2 mRNA and is predicted to cause the premature termination of BRCA2 protein synthesis. Although it is located in the last exon of BRCA2 and is not expected to undergo nonsense-mediated decay, the variant removes the last 194 residues of the BRCA2 protein including the RAD51-interaction region involved in recombination-mediated DNA repair (PMID: 17515903 (2007)). The frequency of this variant in the general population, 0.000004 (1/249592 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 32341426 (2020), 25452441 (2015), 25103822 (2014), 24156927 (2014)), as well as Fanconi anemia (PMIDs: 26740091 (2016), 22720145 (2012), 12065746 (2002)). Based on the available information, this variant is classified as pathogenic. (less)
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329588.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Published functional studies … (more)
Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: cell line with this variant exhibited sensitivity to MMC exposure, increased IR induction of foci (present in both cytoplasm and nucleus) and absent FANCD2/BRCA2 complex in chromatin (Wang 2004); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants are considered pathogenic by a well-established clinical consortium and/or database.; Also known as c.9900dupA; This variant is associated with the following publications: (PMID: 24301060, 28152038, 24156927, 14559878, 16683254, 16115142, 25447315, 25452441, 15689453, 24312913, 11597388, 15645491, 22921157, 26846091, 26740091, 22720145, 29922827, 29446198, 29753700, 30720243, 30291343, 32341426, 30787465, 31076742, 35216584, 12065746, 15199141, 10733923, 9126738) (less)
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Pathogenic
(Jul 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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BRCA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004119359.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The BRCA2 c.9672dupA variant is predicted to result in a frameshift and premature protein termination (p.Tyr3225Ilefs*30). This variant has been reported in the heterozygous state … (more)
The BRCA2 c.9672dupA variant is predicted to result in a frameshift and premature protein termination (p.Tyr3225Ilefs*30). This variant has been reported in the heterozygous state in multiple individuals with breast and/or ovarian cancer (van der Hout et al. 2006. PubMed ID: 16683254; Karami et al. 2013. PubMed ID: 24312913; Tea et al. 2014. PubMed ID: 24156927; Couch et al. 2014. PubMed ID: 25452441; Rebbeck et al. 2018. PubMed ID: 29446198; Haer-Wigman et al. 2019. PubMed ID: 30291343). This variant has also been reported in the compound heterozygous or homozygous state in individuals with Fanconi anemia (Howlett et al. 2002. PubMed ID: 12065746; Barber et al. 2005. PubMed ID: 16115142). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32972321-T-TA) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126217/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Aug 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004213675.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 05, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000255257.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr3225Ilefs*30) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Tyr3225Ilefs*30) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 194 amino acid(s) of the BRCA2 protein. This variant is present in population databases (rs80359773, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer, medulloblastoma, and Fanconi anemia (PMID: 12065746, 16683254, 24156927, 29753700). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 9900insA. ClinVar contains an entry for this variant (Variation ID: 126217). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRCA2 function (PMID: 12065746). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 10, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004563568.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The BRCA2 c.9672dup; p.Tyr3225IlefsTer30 variant (rs80359773), also known as 9900insA, is reported in multiple individuals and families with hereditary breast and ovarian cancer syndrome and … (more)
The BRCA2 c.9672dup; p.Tyr3225IlefsTer30 variant (rs80359773), also known as 9900insA, is reported in multiple individuals and families with hereditary breast and ovarian cancer syndrome and found compound heterozygous in at least one individual with Fanconi anemia (de Jonge 2019, Howlett 2002, Verhoog 2001). This variant is classified as pathogenic by an expert panel in the ClinVar Database (Variation ID: 126217). It is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This variant results in a premature termination codon in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated BRCA2 protein. Based on available information, this variant is considered to be pathogenic. References: de Jonge MM et al. Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity. Clin Cancer Res. 2019 Dec 15;25(24):7517-7526. PMID: 31492746. Howlett NG et al. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. PMID: 12065746. Verhoog LC et al. Large regional differences in the frequency of distinct BRCA1/BRCA2 mutations in 517 Dutch breast and/or ovarian cancer families. Eur J Cancer. 2001 Nov;37(16):2082-90. PMID: 11597388. (less)
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Pathogenic
(Nov 03, 2014)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Michigan Medical Genetics Laboratories, University of Michigan
Accession: SCV000196029.1
First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014 |
Tissue: Blood
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Pathogenic
(May 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV000803165.1
First in ClinVar: Oct 21, 2017 Last updated: Oct 21, 2017 |
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Pathogenic
(Oct 28, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hereditary breast ovarian cancer syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000605805.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 26, 2017 |
Comment:
The p.Tyr3225fs variant in BRCA2 has been reported in the heterozygous state in >30 individuals with BRCA2-associated cancers and in the compound heterozygous s tate … (more)
The p.Tyr3225fs variant in BRCA2 has been reported in the heterozygous state in >30 individuals with BRCA2-associated cancers and in the compound heterozygous s tate in 1 individual with Fanconi anemia (Howlett 2002, Tea 2014, Hout 2006, Dru sedau 2013, Karami 2013, Breast Cancer Information Core (BIC) database). This va riant was absent from large population studies. This variant is predicted to cau se a frameshift, which alters the protein?s amino acid sequence beginning at pos ition 3225 and leads to a premature termination codon 30 amino acids downstream. Heterozygous loss of function of the BRCA2 gene is an established disease mecha nism in hereditary breast and ovarian cancer (HBOC). In summary, this variant me ets criteria to be classified as pathogenic for HBOC in an autosomal dominant ma nner. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jun 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762267.1
First in ClinVar: Jul 30, 2021 Last updated: Jul 30, 2021 |
Clinical Features:
Breast carcinoma (present)
Sex: female
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Pathogenic
(Feb 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000185507.7
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The c.9672dupA pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a duplication of A at nucleotide position 9672, causing a … (more)
The c.9672dupA pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a duplication of A at nucleotide position 9672, causing a translational frameshift with a predicted alternate stop codon (p.Y3225Ifs*30). This alteration has been reported in multiple individuals and families with breast and/or ovarian cancer (van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Reitsma W et al. Eur. J. Cancer 2013 Jan;49(1):132-41; Tea MK et al. Maturitas 2014 Jan;77(1):68-72; De Talhouet S et al. Sci Rep, 2020 04;10:7073). Further, this alteration was reported in trans with a likely pathogenic BRCA2 missense variant in a patient diagnosed with Fanconi anemia at 2 months of age, who later died of metastatic glioblastoma multiforme at age 4 (Dodgshun AJ et al. Cancer Genet. 2016 209(1-2):53-6). This alteration has also been detected in conjunction with another BRCA2 mutation in cells derived from a patient with Fanconi anemia (Howlett NG et al. Science 2002 Jul;297(5581):606-9; Feng Z et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Jan;108(2):686-91). Of note, this alteration is also designated as 9900insA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. (less)
Number of individuals with the variant: 1
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Pathogenic
(Oct 02, 2015)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
germline
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Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Accession: SCV000328160.4
First in ClinVar: Nov 05, 2016 Last updated: Dec 11, 2022 |
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Likely pathogenic
(Oct 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000911347.4
First in ClinVar: May 19, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant inserts 1 nucleotide in codon 3225 in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the … (more)
This variant inserts 1 nucleotide in codon 3225 in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is also known as 9900insA and c.9672_9673insA in the literature. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the RAD51 binding domain that has been reported to be essential for homologous recombination and DNA repair (PMID: 17515903). Cell lines that are compound heterozygous for this variant and a known pathogenic BRCA2 truncation variant produced a truncated protein consistent with truncation in exon 27 (PMID: 12065746) and exhibited hypersensitivity to mitomycin C and other DNA damaging agents (PMID: 12065746, 16920162). This variant also has been reported in multiple individuals with personal or family history of breast and/or ovarian cancer (PMID: 16683254, 24156927, 25452441, 27153395, Color internal data). This variant has also been reported in three individuals who are compound heterozygous with a pathogenic BRCA2 covariant and affected with Fanconi anemia (PMID: 12065746, 22720145, 26740091). An external laboratory has reported the associated cancer histories of multiple carriers of this variant are inconsistent with known BRCA2 pathogenic variants (https://myriad-web.s3.amazonaws.com/publications/74925948-ACMG%202017%20Mundt%20variant%20classification%20Presented.pdf). This variant has been identified in 1/249592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been observed in multiple individuals and families affected with BRCA2-related phenotypes. Although additional studies are necessary to determine the role of this variant in disease and penetrance conclusively, this variant is classified as Likely Pathogenic based on the available evidence. (less)
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Likely Pathogenic
(Feb 24, 2023)
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criteria provided, single submitter
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004846215.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
This variant inserts 1 nucleotide in codon 3225 in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the … (more)
This variant inserts 1 nucleotide in codon 3225 in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is also known as 9900insA and c.9672_9673insA in the literature. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant is expected to disrupt the RAD51 binding domain that has been reported to be essential for homologous recombination and DNA repair (PMID: 17515903). Cell lines that are compound heterozygous for this variant and a known pathogenic BRCA2 truncation variant produced a truncated protein consistent with truncation in exon 27 (PMID: 12065746) and exhibited hypersensitivity to mitomycin C and other DNA damaging agents (PMID: 12065746, 16920162). This variant also has been reported in multiple individuals with personal or family history of breast and/or ovarian cancer (PMID: 16683254, 24156927, 25452441, 27153395, Color internal data). This variant has also been reported in three individuals who are compound heterozygous with a pathogenic BRCA2 covariant and affected with Fanconi anemia (PMID: 12065746, 22720145, 26740091). An external laboratory has reported the associated cancer histories of multiple carriers of this variant are inconsistent with known BRCA2 pathogenic variants (https://myriad-web.s3.amazonaws.com/publications/74925948-ACMG%202017%20Mundt%20variant%20classification%20Presented.pdf). This variant has been identified in 1/249592 chromosomes in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been observed in multiple individuals and families affected with BRCA2-related phenotypes. Although additional studies are necessary to determine the role of this variant in disease and penetrance conclusively, this variant is classified as Likely Pathogenic based on the available evidence. (less)
Number of individuals with the variant: 1
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000733341.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Pathogenic
(Jul 26, 2002)
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no assertion criteria provided
Method: literature only
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FANCONI ANEMIA, COMPLEMENTATION GROUP D1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000030143.4
First in ClinVar: Apr 04, 2013 Last updated: May 21, 2018 |
Comment on evidence:
In the Fanconi anemia complementation group D1 (FANCD1; 605724) reference cell line EUFA423, Howlett et al. (2002) found a 9900insA mutation in the BRCA2 gene … (more)
In the Fanconi anemia complementation group D1 (FANCD1; 605724) reference cell line EUFA423, Howlett et al. (2002) found a 9900insA mutation in the BRCA2 gene in compound heterozygosity with 7691insAT (600185.0018). The 9900insA mutant allele was previously identified in a breast cancer kindred (Breast Cancer Linkage Consortium, 1999). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956712.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(May 29, 2002)
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no assertion criteria provided
Method: clinical testing
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Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
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Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000147696.1
First in ClinVar: Apr 04, 2014 Last updated: Apr 04, 2014 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Geographic origin: Western European
Observation 3:
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Netherlands
Observation 4:
Number of individuals with the variant: 1
Ethnicity/Population group: Central/Eastern European
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Malignant tumor of breast
Affected status: yes
Allele origin:
unknown
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Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000592302.2 First in ClinVar: Oct 11, 2015 Last updated: Apr 13, 2021 |
Comment:
The BRCA2 p.Tyr3225IlefsX30 variant was identified in individuals with hereditary breast and ovarian cancer (Karami 2013, Vos 2014) in the Netherlands populations and in Fanconi … (more)
The BRCA2 p.Tyr3225IlefsX30 variant was identified in individuals with hereditary breast and ovarian cancer (Karami 2013, Vos 2014) in the Netherlands populations and in Fanconi Anemia patients (Barber 2005, Howlett 2002, Lee 2014, Offit 2003, Reid 2005¬, Wang 2004), although no frequency data was given. The variant was also identified in dbSNP (ID: rs80359773) as “With Pathogenic allele”, Clinvitae database (pathogenic, Invitae), ARUP Laboratories BRCA Mutations Database (as definitely pathogenic), the ClinVar database (pathogenic, by multiple submitters), GeneInsight COGR database (unclassified) the BIC database (4x with unknown clinical importance), and UMD (3x with a “causal” classification). The c.9672dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3225 and leads to a premature stop codon at position 3254. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001905702.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002035341.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical outcome of breast cancer in carriers of BRCA1 and BRCA2 mutations according to molecular subtypes. | De Talhouet S | Scientific reports | 2020 | PMID: 32341426 |
Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. | Waszak SM | The Lancet. Oncology | 2018 | PMID: 29753700 |
Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. | Rebbeck TR | Human mutation | 2018 | PMID: 29446198 |
Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. | LaDuca H | PloS one | 2017 | PMID: 28152038 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Whole-exome sequencing is a powerful approach for establishing the etiological diagnosis in patients with intellectual disability and microcephaly. | Rump P | BMC medical genomics | 2016 | PMID: 26846091 |
Biallelic FANCD1/BRCA2 mutations predisposing to glioblastoma multiforme with multiple oncogenic amplifications. | Dodgshun AJ | Cancer genetics | 2016 | PMID: 26740091 |
Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. | Couch FJ | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25452441 |
Variation in mutation spectrum partly explains regional differences in the breast cancer risk of female BRCA mutation carriers in the Netherlands. | Vos JR | Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology | 2014 | PMID: 25103822 |
Central European BRCA2 mutation carriers: birth cohort status correlates with onset of breast cancer. | Tea MK | Maturitas | 2014 | PMID: 24156927 |
A comprehensive focus on global spectrum of BRCA1 and BRCA2 mutations in breast cancer. | Karami F | BioMed research international | 2013 | PMID: 24312913 |
PGD for hereditary breast and ovarian cancer: the route to universal tests for BRCA1 and BRCA2 mutation carriers. | Drüsedau M | European journal of human genetics : EJHG | 2013 | PMID: 23531862 |
Support of the 'fallopian tube hypothesis' in a prospective series of risk-reducing salpingo-oophorectomy specimens. | Reitsma W | European journal of cancer (Oxford, England : 1990) | 2013 | PMID: 22921157 |
Diagnosis of fanconi anemia: mutation analysis by next-generation sequencing. | Ameziane N | Anemia | 2012 | PMID: 22720145 |
BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. | Alsop K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2012 | PMID: 22711857 |
Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. | Kuznetsov SG | Nature medicine | 2008 | PMID: 18607349 |
A syngeneic variance library for functional annotation of human variation: application to BRCA2. | Hucl T | Cancer research | 2008 | PMID: 18593900 |
Interaction with the BRCA2 C terminus protects RAD51-DNA filaments from disassembly by BRC repeats. | Davies OR | Nature structural & molecular biology | 2007 | PMID: 17515903 |
Inherited association of breast and colorectal cancer: limited role of CHEK2 compared with high-penetrance genes. | Naseem H | Clinical genetics | 2006 | PMID: 17026620 |
Cellular characterization of cells from the Fanconi anemia complementation group, FA-D1/BRCA2. | Godthelp BC | Mutation research | 2006 | PMID: 16920162 |
A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. | van der Hout AH | Human mutation | 2006 | PMID: 16683254 |
Inherited FANCD1/BRCA2 exon 7 splice mutations associated with acute myeloid leukaemia in Fanconi anaemia D1 are not found in sporadic childhood leukaemia. | Barber LM | British journal of haematology | 2005 | PMID: 16115142 |
Biallelic inactivation of BRCA2 in Fanconi anemia. | Howlett NG | Science (New York, N.Y.) | 2002 | PMID: 12065746 |
Cancer risks in BRCA2 mutation carriers. | Breast Cancer Linkage Consortium | Journal of the National Cancer Institute | 1999 | PMID: 10433620 |
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Text-mined citations for rs80359773 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.