ClinVar Genomic variation as it relates to human health
NM_000251.3(MSH2):c.1A>C (p.Met1Leu)
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_000251.3(MSH2):c.1A>C (p.Met1Leu)
Variation ID: 90832 Accession: VCV000090832.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p21 2: 47403192 (GRCh38) [ NCBI UCSC ] 2: 47630331 (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 Mar 24, 2015 Feb 20, 2024 Jun 21, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000251.3:c.1A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000242.1:p.Met1Leu missense initiator codon variant NM_001258281.1:c.-31+17A>C intron variant NC_000002.12:g.47403192A>C NC_000002.11:g.47630331A>C NG_007110.2:g.5069A>C LRG_218:g.5069A>C LRG_218t1:c.1A>C LRG_218p1:p.Met1Leu - Protein change
- M1L
- Other names
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- Canonical SPDI
- NC_000002.12:47403191:A:C
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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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MSH2 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
7207 | 7355 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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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Uncertain significance (1) |
reviewed by expert panel
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Jun 21, 2019 | RCV000076334.7 | |
Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV000160588.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Dec 16, 2015 | RCV000409939.3 | |
Likely benign (1) |
criteria provided, single submitter
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Aug 28, 2023 | RCV000505793.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV000524369.10 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000656870.9 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001358333.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 1, 2022 | RCV002498368.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 27, 2023 | RCV003407454.4 |
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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Uncertain significance
(Jun 21, 2019)
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reviewed by expert panel
Method: curation
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Lynch syndrome
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000107358.4
First in ClinVar: Dec 19, 2013 Last updated: Sep 03, 2023 |
Comment:
Insufficient evidence
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Uncertain significance
(Feb 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Muir-Torré syndrome Mismatch repair cancer syndrome 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002806885.2
First in ClinVar: Dec 31, 2022 Last updated: Sep 03, 2023 |
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Uncertain significance
(Mar 29, 2023)
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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: SCV000214177.9
First in ClinVar: Mar 24, 2015 Last updated: Sep 03, 2023 |
Comment:
The p.M1? variant (also known as c.1A>C) is located in coding exon 1 of the MSH2 gene and results from an A to C substitution … (more)
The p.M1? variant (also known as c.1A>C) is located in coding exon 1 of the MSH2 gene and results from an A to C substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. Translation initiation may occur through use of CUG at the original start codon or may lead to a protein with a N-terminal truncation of 25 amino acids due to the presence of another downstream methionine at codon 26 (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). Studies of this truncated MSH2 (NΔ25) protein reflect an impaired ability to bind and cleave ATP, although it retains its ability to heterodimerize with MSH6 and MSH3 and it can still bind to mismatched DNA, albeit at a reduced rate (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). Transfection of a cDNA containing the c.1A>C alteration into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in mismatch repair activity (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51:647-58). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts; however, tumors do not consistently demonstrate microsatellite instability and abnormal immunohistochemical staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep;63:749-59; Otway R et al. Hum. Mutat. 2000;16:61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354:2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29:367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90; Chubb D et al. J. Clin. Oncol., 2015 Feb;33:426-32; Grant RC et al. Gastroenterology, 2015 Mar;148:556-64; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). In another study, two siblings without constitutional mismatch repair deficiency (CMMRD) syndrome were reported to be compound heterozygous for an MSH2 start codon alteration and an MSH2 gross deletion and had an unusually severe Lynch tumor burden (Kets CM et al. Eur. J. Hum. Genet. 2009 Feb;17:159-64). This alteration has also been seen in a compound heterozygous state with an MSH2 truncation mutation in an individual who reportedly did not have features of CMMRD (Rosenthal ET et al. Clin. Genet. 2015 Dec;88:533-41). This amino acid position is highly conserved in available vertebrate species. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. (less)
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Likely benign
(Aug 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001370668.3
First in ClinVar: Jul 16, 2020 Last updated: Sep 03, 2023 |
Comment:
Variant summary: MSH2 c.1A>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded … (more)
Variant summary: MSH2 c.1A>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream methionine codon located 26 residues into the protein sequence. To our knowledge no pathogenic variants upstream of this alternate methionine codon 26 have been reported. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 214958 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (Lynch syndrome), allowing no conclusion about variant significance. c.1A>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (HNPCC) (Otway_2000), MSI low sigmoid colon tumor who did not fulfill both the modified Amsterdam and Bethesda criteria (Barnetson_2006 and 2008), Ovarian cancer who did not meet the Bethesda criteria for HNPCC (Cyr_2012), epithelial ovarian cancer (Pal_2012), serous and/or non-serous ovarian cancer (Kim_2020), colorectal cancer (Rosenthal_2015, DeRycke_2017), breast cancer (Desmond_2015), and diffuse gastric cancer (Fewings_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least two co-occurrences in trans with other pathogenic variant(s) have been reported in individuals with no evidence of constitutional mismatch repair deficiency (CMMRD) (MSH2 exons 1-6del and MSH2 c.2038C>T, p.Arg680* in Rosenthal_2015). Furthermore, a recent study lists this variant as a VUS identified in a mismatch repair (MMR) proficient individual with colorectal cancer and a family history of colon cancer (mother at age 78) and Lymphoma/breast cancer (sister aged 50s), who harbored two additional pathogenic variants in the ATM (c.5932C>T, p.Glu1978*) and BRIP1 (c.1871C>A, p.Ser624*) genes (Pearlman_2021). These reports collectively provide convincing evidence for a non-causative/benign role attributed to this variant. At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a partially functional mismatch repair activity using a lentiviral expression system (Cyr_2012) while another study reported a functionally neutral outcome in a massively parallel assay system measuring sensitivity to 6-thioguanine(6-TG) (Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 16807412, 21837758, 28944238, 26270727, 9718327, 29706558, 32809219, 10874307, 23047549, 34250417, 25639900, 33357406). Multiple clinical diagnostic laboratories and one expert panel (InSiGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=8; Likely benign, n=1). Some of the submitters have provided overlapping evidence utilized in the context of this evaluation. Based on the published clinical and functional evidence spanning over 13 years (2008-2021) as outlined above, the variant was re-classified as likely benign. (less)
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Uncertain significance
(Jan 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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MSH2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004115986.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MSH2 c.1A>C variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in individuals with ovarian (Pal et … (more)
The MSH2 c.1A>C variant is predicted to disrupt the translation initiation site (Start loss). This variant has been reported in individuals with ovarian (Pal et al. 2012. PubMed ID: 23047549), pancreatic (Table S1, Grant et al. 2015. PubMed ID: 25479140), prostate (Table S1, Nguyen-Dumont et al. 2020. PubMed ID: 32338768), colorectal (Barnetson et al. 2008. PubMed ID: 18033691; Table S1, DeRycke et al. 2017. PubMed ID: 28944238), and gastric cancers (Fewings et al. 2018. PubMed ID: 29706558). Disruptions of the MSH2 start codon in the NM_000251 transcript have been shown to result in a truncated MSH2 protein lacking the first 25 amino acids and biochemically confirmed to result in multiple protein products (in human cell lines) that may include the truncated and full-length forms of MSH2 and to reduce MMR efficiency slightly (Farrington et al. 1998. PubMed ID: 9718327; Cyr et al. 2012. PubMed ID: 21837758). However, the loss of MSH2 start codon has also been reported in at least three individuals without clinical features of constitutional mismatch repair deficiency syndrome, who had other pathogenic MSH2 variants in trans (Kets et al. 2009. PubMed ID: 18781192; Rosenthal et al. 2015. PubMed ID: 25639900). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47630331-A-C) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90832/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jun 07, 2023)
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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: SCV000601448.5
First in ClinVar: Sep 28, 2017 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts the translation initiation codon of the MSH2 mRNA and is predicted to interfere with MSH2 protein synthesis. In the published literature, this … (more)
This variant disrupts the translation initiation codon of the MSH2 mRNA and is predicted to interfere with MSH2 protein synthesis. In the published literature, this variant has been reported in multiple patients with early onset colorectal cancer, hereditary nonpolyposis colorectal cancer (HNPCC) patients, pancreatic cancer, hereditary diffuse gastric cancer and ovarian cancer (PMID: 9718327 (1998), 23047549 (2012), 25479140 (2015), 25559809 (2015), 28944238 (2017) and 29706558 (2018)). As evidence suggests, however, this variant is predicted not to cause the classic Lynch syndrome as colon cancer tumors that carry this variant are usually microsatellite instability-low (MSI-Low) (PMID: 18033691 (2008)). In addition, another start-loss variant in MSH2 (c.1A>G) has been previously reported in two siblings who were compound heterozygotes with another pathogenic germline mutation. According to this case report, while both siblings had multiple cancers related to Lynch Syndrome, neither had Constitutional Mismatch Repair Deficiency Syndrome (PMID: 18781192 (2009)). Functional studies have shown that cells carrying this variant produce both the full length protein and a truncated form of the MSH2 protein (an MSH2 protein with the first 25 amino acids deleted). The shorter protein has been shown to have a modest biochemical defect. These studies have also shown that the cells carrying this variant have a small but statistically significant reduction in mismatch repair (MMR) efficiency as compared to wild type cells (PMID: 21837758 (2012)). The frequency of this variant in the general population, 0.00012 (13/110908 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain significance
(Nov 27, 2023)
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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: SCV000902903.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This variant alters the translation initiation codon methionine at codon 1 of the MSH2 protein. A functional study has shown that leucine encoded by c.1A>C … (more)
This variant alters the translation initiation codon methionine at codon 1 of the MSH2 protein. A functional study has shown that leucine encoded by c.1A>C variant could serve as a translation initiation site and results in the production of a full length protein that exhibits near normal activity (PMID: 21837758). In another functional study, the Met1Leu variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). It has also been shown that a downstream methionine at codon 26 may serve as an alternate translation initiation site at low levels and that recombinant MSH2 protein lacking the first 25 amino acids were largely functional (PMID: 21837758). An alternative MSH2 transcript (NM_001258281) lacking the first 66 amino acids of the primary transcript, is expressed at similar or higher levels in human tissues (https://gnomad.broadinstitute.org/). This variant has been observed in an individual affected with ovarian cancer with multiple Lynch syndrome-associated cancers in the family (PMID: 21837758), and an individual affected with early onset colorectal cancer (PMID: 28944238). A study of 14 carriers from eight families has suggested that the presence of this variant does not appear to be diagnostic of Lynch syndrome (PMID: 25639900). This variant has been observed in individuals affected with breast, prostate, pancreatic, and lung cancer (PMID: 25479140, 29625052, 32338768, 33471991), as well as in healthy unaffected individuals (PMID: 33471991). This variant has been identified in 13/246250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166271.15
First in ClinVar: Jun 23, 2014 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. It is unclear whether it … (more)
This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 26 has the potential to rescue this variant. This variant is present in population databases (rs267607911, gnomAD 0.01%). Disruption of the initiator codon has been observed in individual(s) with lung cancer, ovarian cancer (PMID: 34326862, 36451132). Disruption of the initiator codon has been observed on the opposite chromosome (in trans) from a pathogenic variant in MSH2 in at least one individual (PMID: 25639900), which suggests that this variant may not be disease-causing. ClinVar contains an entry for this variant (Variation ID: 90832). 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 disruption of the initiator codon affects MSH2 function (PMID: 21837758). Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(May 22, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002534436.2
First in ClinVar: Jun 24, 2022 Last updated: Sep 03, 2023 |
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Uncertain significance
(Dec 16, 2015)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000487978.3
First in ClinVar: Jan 06, 2017 Last updated: Sep 03, 2023 |
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Uncertain significance
(Aug 15, 2023)
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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: SCV000211183.11
First in ClinVar: Feb 24, 2015 Last updated: Sep 03, 2023 |
Comment:
Initiator codon variant shown to produce multiple protein products including a full-length and a truncated transcript missing the first 25 amino acids through use of … (more)
Initiator codon variant shown to produce multiple protein products including a full-length and a truncated transcript missing the first 25 amino acids through use of an in-frame alternate start codon (Cyr et al., 2012); Published functional studies are inconclusive: Demonstrated impaired DNA binding and mismatch repair activity, but had no effect on MSH6 or MSH3 interaction (Cyr et al., 2012); Observed in individuals with MSH2-related cancers; however, tumor studies have shown microsatellite stability (MSS) or low levels of instability (MSI-L), and no loss of MSH2 protein expression (Otway et al., 2000; Parc et al., 2003; Barnetson et al., 2006; Barnetson et al., 2008; Pal et al., 2012; Cyr et al., 2012; Chubb et al., 2015; Grant et al., 2015; Fewings et al., 2018); This variant is associated with the following publications: (PMID: 12624141, 27476653, 10874307, 16807412, 18033691, 18781192, 23047549, 27064304, 24302565, 27153395, 28779004, 27449771, 28944238, 9718327, 25479140, 25559809, 29706558, 30728895, 26270727, 32338768, 29625052, 21837758, 18822302, 21120944, 22814378, 25639900, 34541770, 33471991, 36451132, 34326862) (less)
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Uncertain significance
(-)
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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: SCV001554037.2 First in ClinVar: Apr 13, 2021 Last updated: Sep 03, 2023 |
Comment:
The MSH2 p.Met1? variant was identified in 5 of 8838 proband chromosomes (frequency: 0.001) from individuals or families with ovarian, colorectal, or pancreatic cancer and … (more)
The MSH2 p.Met1? variant was identified in 5 of 8838 proband chromosomes (frequency: 0.001) from individuals or families with ovarian, colorectal, or pancreatic cancer and was not identified in 2844 control chromosomes from healthy individuals (Barnetson 2008, DeRycke 2017, Grant 2015, Otway 2000, Pal 2012). The variant was also identified in dbSNP (ID: rs267607911) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by InSight, Invitae, GeneDx, Ambry Genetics, Counsyl and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae, UMD-LSDB (1x as causal), Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors (2x uncertain significance). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, or Zhejiang University databases. The variant was identified in control databases in 11 of 208952 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant observed in European population in 11 of 93132 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1A>C p.Met1? variant occurs in the first base of the translation initiation site (the Methionine amino acid start site), increasing the likelihood this variant may disrupt translation or lead to an abnormal protein product. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. An in vivo MMR assay by Cyr (2012) suggests the variant may have a moderate impact on disease phenotype. This alteration leads to the production of multiple protein products in human cells that may include the truncated and full-length forms of MSH2. Production of functional protein occurs through use of an alternative start codon at codon 26. In addition, the later study by Rosenthal (2015) published the case of two siblings with this variant in trans with a deletion of exons 1–6 in MSH2, and no reported features of CMMR-D, and in trans with the pathogenic variant MSH2 c.2038C>T (p.Arg680*) in patient without reported features of CMMR-D. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
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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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- | - | - | - | PMID: 10874307 |
- | - | - | - | PMID: 12624141 |
- | - | - | - | PMID: 16807412 |
- | - | - | - | PMID: 18033691 |
- | - | - | - | PMID: 18781192 |
- | - | - | - | PMID: 21837758 |
- | - | - | - | PMID: 23047549 |
- | - | - | - | PMID: 25479140 |
- | - | - | - | PMID: 25559809 |
- | - | - | - | PMID: 25639900 |
- | - | - | - | PMID: 26270727 |
- | - | - | - | PMID: 28944238 |
- | - | - | - | PMID: 29625052 |
- | - | - | - | PMID: 29706558 |
- | - | - | - | PMID: 32338768 |
- | - | - | - | PMID: 32809219 |
- | - | - | - | PMID: 33357406 |
- | - | - | - | PMID: 33471991 |
- | - | - | - | PMID: 34250417 |
- | - | - | - | PMID: 34326862 |
- | - | - | - | PMID: 36451132 |
- | - | - | - | PMID: 9718327 |
http://www.insight-database.org/classifications/?gene=MSH2&variant=c.1A%3EC | - | - | - | - |
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Text-mined citations for rs267607911 ...
HelpRecord last updated Mar 11, 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.