Total submissions: 14
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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, |
RCV000075031 | SCV000266212 | uncertain significance | Lynch syndrome | 2015-11-20 | criteria provided, single submitter | clinical testing | |
Laboratory for Molecular 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, |
RCV000417385 | SCV000595848 | likely benign | not specified | 2020-02-06 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV000115442 | SCV000690476 | likely benign | Hereditary cancer-predisposing syndrome | 2015-04-07 | criteria provided, single submitter | clinical testing | |
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, |
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, |
RCV000115442 | SCV002536351 | likely benign | Hereditary cancer-predisposing syndrome | 2021-05-19 | criteria provided, single submitter | curation | |
Center for Genomic Medicine, |
RCV000417385 | SCV002552266 | likely benign | not specified | 2023-08-15 | criteria provided, single submitter | clinical testing | |
Preventiongenetics, |
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, |
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 + |