ClinVar Genomic variation as it relates to human health
NM_000059.4(BRCA2):c.1244A>G (p.His415Arg)
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.
Uncertain significance(8); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000059.4(BRCA2):c.1244A>G (p.His415Arg)
Variation ID: 51090 Accession: VCV000051090.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 13q13.1 13: 32332722 (GRCh38) [ NCBI UCSC ] 13: 32906859 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 1, 2014 May 1, 2024 Jan 25, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000059.4:c.1244A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000050.3:p.His415Arg missense NC_000013.11:g.32332722A>G NC_000013.10:g.32906859A>G NG_012772.3:g.22243A>G LRG_293:g.22243A>G LRG_293t1:c.1244A>G LRG_293p1:p.His415Arg U43746.1:n.1472A>G - Protein change
- H415R
- Other names
- p.H415R:CAT>CGT
- Canonical SPDI
- NC_000013.11:32332721:A:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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 | ||
---|---|---|---|---|---|---|
HI score
Help
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. |
|||
BRCA2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
18726 | 18884 |
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. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Aug 23, 2023 | RCV000112899.8 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 19, 2021 | RCV000160035.10 | |
Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
|
Mar 23, 2023 | RCV000165768.15 | |
Uncertain significance (1) |
no assertion criteria provided
|
Jan 29, 2014 | RCV000735440.1 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 3, 2022 | RCV000780016.4 | |
Likely benign (1) |
criteria provided, single submitter
|
Jan 25, 2024 | RCV001084688.5 |
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. |
|
---|---|---|---|---|---|
Uncertain significance
(Mar 23, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488424.2
First in ClinVar: Apr 01, 2014 Last updated: Dec 24, 2022 |
|
|
Likely benign
(Sep 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000903093.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
|
|
Uncertain significance
(Nov 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046114.1
First in ClinVar: Jan 01, 2022 Last updated: Jan 01, 2022 |
|
|
Uncertain significance
(Apr 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000210265.16
First in ClinVar: Feb 24, 2015 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Also known as 1472A>G; Observed in individuals with breast and/or ovarian cancer, pancreatic cancer, as well as, unaffected controls (Wong-Brown 2015, Alemar 2017, Momozawa 2018, Zuntini 2018, Mizukami 2020, Santonocito 2020); This variant is associated with the following publications: (PMID: 10923033, 25682074, 29161300, 30254663, 32438681, 30287823, 32980694) (less)
|
|
Likely benign
(Mar 23, 2023)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV003849937.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023
Comment:
BRCA2 exon 10 coldspot. Reclassification based on statistical prior probability.
|
Comment:
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
|
|
Likely benign
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary breast ovarian cancer syndrome
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000071779.15
First in ClinVar: Jul 03, 2013 Last updated: Feb 14, 2024 |
|
|
Uncertain significance
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002517966.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
Uncertain significance
(Sep 19, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002533219.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The BRCA2 c.1244A>G (p.H415R) variant has been reported individuals with breast and/or ovarian cancer (PMID: 32438681, 30254663, 30254663, 25682074). It is reported in 3/60,466 women … (more)
The BRCA2 c.1244A>G (p.H415R) variant has been reported individuals with breast and/or ovarian cancer (PMID: 32438681, 30254663, 30254663, 25682074). It is reported in 3/60,466 women with breast cancer and 2/53,461 controls by a large case-control study (PMID 33471991). This variant was observed in 4/128564 chromosomes in the Non-Finnish European population, according to the Genome Aggregation Database (PMID: 32461654). This variant has been reported in ClinVar (Variation ID 51090). This amino acid position is not well conserved in available vertebrate species. Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The overall evidence is insufficient to meet ACMG/AMP criteria for classifying it as benign or pathogenic. In summary, the clinical significance of this variant is currently uncertain. (less)
|
|
|
Uncertain significance
(Oct 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917010.3
First in ClinVar: Jun 02, 2019 Last updated: Nov 19, 2022 |
Comment:
Variant summary: BRCA2 c.1244A>G (p.His415Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign … (more)
Variant summary: BRCA2 c.1244A>G (p.His415Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249452 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1244A>G has been reported in the literature as a VUS in individuals undergoing testing for Breast and/or Ovarian Cancer (example, Alemar_2017, Momozawa_2018, Wong-Brown_2015, Zuntini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been reported in the UMD database (BRCA1 c.3979C>T, p.Gln1327Ter), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
|
|
Uncertain significance
(Dec 31, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761582.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
Insufficient evidence
|
|
Likely Benign
(Aug 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004846888.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Number of individuals with the variant: 4
|
|
Uncertain significance
(May 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000216513.7
First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024 |
Comment:
The p.H415R variant (also known as c.1244A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide … (more)
The p.H415R variant (also known as c.1244A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1244. The histidine at codon 415 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported in a cohort of 418 Brazilian individuals who met NCCN genetic testing guidelines for hereditary breast and ovarian cancer (Alemar B et al. PLoS One, 2017 Nov;12:e0187630). This alteration has also been identified in individuals diagnosed with breast and/or ovarian cancer (Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80; Zuntini R et al. Front Genet, 2018 Sep;9:378; Santonocito C et al. Cancers (Basel), 2020 May;12:). This alteration was also observed with an allele frequency of 0.00071 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.0003 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0003 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
Uncertain significance
(Dec 23, 2003)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial 2
Affected status: yes
Allele origin:
germline
|
Breast Cancer Information Core (BIC) (BRCA2)
Accession: SCV000145839.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014 |
Number of individuals with the variant: 1
Ethnicity/Population group: Western European
|
|
Likely benign
(Sep 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
germline
|
Department of Medical and Surgical Sciences, University of Bologna
Accession: SCV004228364.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
|
|
Uncertain significance
(Jan 29, 2014)
|
no assertion criteria provided
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV000863576.1 First in ClinVar: Dec 24, 2018 Last updated: Dec 24, 2018 |
|
|
Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
Breast-ovarian cancer, familial, susceptibility to, 2
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001554187.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The BRCA2 p.His415Arg variant was identified in 2 of 1506 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alemar 2017, … (more)
The BRCA2 p.His415Arg variant was identified in 2 of 1506 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alemar 2017, Wong 2015). The variant was also identified in large population study by Momozawa (2018) in 5 of 14102 female chromosomes (frequency: 0.0004), and 7 in 22482 female control chromosomes (frequency: 0.0003) and 4 in 24980 male control chromosomes (frequency: 0.0002). The variant was also identified in dbSNP (ID: rs80358417) as "With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Color; as uncertain significance by six submitters), LOVD 3.0 (6x), and UMD-LSDB (9x as likely neutral). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.3979C>T(p.Gln1327X)), increasing the likelihood that the p.His415Arg variant does not have clinical significance. The variant was also identified by our laboratory in 1 individual with pancreatic cancer, co-occurring with a pathogenic BRCA1 variant (c.5278-?_5592+?del, p.Ile1760_His1862delins37), further increasing the likelihood this variant has little clinical significance. The variant was identified in control databases in 5 of 275910 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6428 chromosomes (freq: 0.0002), European in 4 of 126226 chromosomes (freq: 0.00003); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.His415 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. | Santonocito C | Cancers | 2020 | PMID: 32438681 |
Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". | Dines JN | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 31911673 |
Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. | Momozawa Y | Nature communications | 2018 | PMID: 30287823 |
Dealing With BRCA1/2 Unclassified Variants in a Cancer Genetics Clinic: Does Cosegregation Analysis Help? | Zuntini R | Frontiers in genetics | 2018 | PMID: 30254663 |
BRCA1 and BRCA2 mutational profile and prevalence in hereditary breast and ovarian cancer (HBOC) probands from Southern Brazil: Are international testing criteria appropriate for this specific population? | Alemar B | PloS one | 2017 | PMID: 29161300 |
Rapid and cost-effective high-throughput sequencing for identification of germline mutations of BRCA1 and BRCA2. | Ahmadloo S | Journal of human genetics | 2017 | PMID: 28179634 |
Prevalence of BRCA1 and BRCA2 germline mutations in patients with triple-negative breast cancer. | Wong-Brown MW | Breast cancer research and treatment | 2015 | PMID: 25682074 |
The breast cancer information core: database design, structure, and scope. | Szabo C | Human mutation | 2000 | PMID: 10923033 |
Text-mined citations for rs80358417 ...
HelpRecord last updated May 19, 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.