ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.73G>T (p.Ala25Ser)

gnomAD frequency: 0.00023  dbSNP: rs267608026
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417385 SCV000149351 likely benign not specified 2017-09-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115442 SCV000186605 likely benign Hereditary cancer-predisposing syndrome 2019-01-16 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001082180 SCV000219021 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-25 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000075031 SCV000266212 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000417385 SCV000539705 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in HGMD, classified as DM?. It has been seen in 2 breast cancer families. In one in vitro study the variant was shown to be mismatch repair proficient. In another paper it is predicted to be neutral. The variant has a Max MAF of 0.03% in ExAC (16 alleles) and 0.03% in gnomAD (35 alleles). It is classified with 3 stars in ClinVar as VUS by an expert panel (InSiGHT) and U Wash, and as Likely benign by GeneDx, Invitae, and Ambry. This region is not conserved and 2 mammals have a Ser at this position.
Genetic Services Laboratory, University of Chicago RCV000417385 SCV000595848 likely benign not specified 2020-02-06 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115442 SCV000690476 likely benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000765674 SCV000897016 uncertain significance Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000417385 SCV000919764 likely benign not specified 2023-06-05 criteria provided, single submitter clinical testing Variant summary: MSH6 c.73G>T (p.Ala25Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 242354 control chromosomes, predominantly at a frequency of 0.00029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.73G>T has been reported in the literature in individuals evaluated for Hereditary Nonpolyposis Colorectal Cancer (e.g. Nilbert_2009, Jori_2015, Houlleberghs_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another potentially pathogenic variant has been reported at least twice (MSH6 c.2926_2929dupCGTT in Jori_2015 and MSH6 c.3103C>T/p.Arg1035X internal testing), providing supporting evidence for a benign role. The variant has also been reported in individuals with other cancer phenotypes (e.g. Wasielewski_2009, Shindo_2017) and healthy controls (e.g. Wasielewski_2009). At least two independent publications report experimental evidence that the variant does not affect normal function of MSH6 (e.g. Drost_2011, Houlleberghs_2017). The following publications have been ascertained in the context of this evaluation (PMID: 35904628, 22102614, 34445333, 28531214, 26517685, 18566915, 28767289, 19924528). Eleven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3) or likely benign (n=8). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000524214 SCV001134455 likely benign not provided 2018-09-10 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115442 SCV002536351 likely benign Hereditary cancer-predisposing syndrome 2021-05-19 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000417385 SCV002552266 likely benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Preventiongenetics, part of Exact Sciences RCV003398661 SCV004103519 uncertain significance MSH6-related condition 2023-05-31 criteria provided, single submitter clinical testing The MSH6 c.73G>T variant is predicted to result in the amino acid substitution p.Ala25Ser. This variant has been seen in individuals with breast or colorectal cancer (Nilbert et al. 2008. PubMed ID: 18566915; Wasielewski et al. 2009. PubMed ID: 19924528; Table S1 - Shirts et al. 2016. PubMed ID: 26845104; Table S2 - Houlleberghs et al. 2017. PubMed ID: 28531214), and an individual with pancreatic ductal adenocarcinoma and a family history of breast cancer (Shindo et al. 2017. PubMed ID: 28767289). In an individual with endometrial cancer this variant was detected in an individual with a different pathogenic variant in MSH6 (Jóri et al. 2015. PubMed ID: 26517685). Functional studies indicate this variant does not impact MSH6 function (Drost et al. 2012. PubMed ID: 22102614; Table S2 - Houlleberghs et al. 2017. PubMed ID: 28531214). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-48010445-G-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89562/). Although we suspect this variant is benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV003482130 SCV004227965 likely benign Hereditary breast ovarian cancer syndrome 2023-11-14 criteria provided, single submitter curation REVEL: 0.076 (BP4), approximately 2-fold of the estimated maximal expected allele (BS1_sup), BS3, PMID: 28531214: not identified as MMR abrogating. According to the ACMG standard criteria we chose these criteria: BP4 (supporting benign): REVEL: 0.076 (BP4), , BS1 (supporting benign): The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer phenotype, BS3 (strong benign): PMID: 28531214: not identified as MMR abrogating PMID: 22102614: In vitro MMR +

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