ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3832C>A (p.Pro1278Thr) (rs587782109)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130625 SCV000185501 likely benign Hereditary cancer-predisposing syndrome 2020-02-07 criteria provided, single submitter clinical testing Other data supporting benign classification;Other strong data supporting benign classification
Invitae RCV001086478 SCV000218656 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000589175 SCV000279324 uncertain significance not provided 2021-08-03 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with a personal or family history of breast, prostate, or colorectal cancer (Tung 2015, Abe 2019, Dharwadkar 2020); This variant is associated with the following publications: (PMID: 33359728, 31391288, 25186627, 30883245)
Color Health, Inc RCV000130625 SCV000685448 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-22 criteria provided, single submitter clinical testing This missense variant replaces proline with threonine at codon 1278 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Lynch syndrome-associated cancer (PMID: 31391288), an individual not affected with cancer who has a family history of various cancers (PMID: 30883245). This variant also has been reported in three individuals affected with breast and/or ovarian cancer, in which two carriers also have a pathogenic CHEK2 covariant (PMID: 25186627). This variant has been identified in 26/250902 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001260255 SCV000695891 likely benign not specified 2020-09-16 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3832C>A (p.Pro1278Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250902 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3-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 Latino origin. c.3832C>A has been reported in the literature in individuals affected with cancer including breast and ovarian cancer (e.g. Tung 2015, Li_2020) but it was also reported in an individual with no personal history of cancer who was above the average age of onset for Hereditary Nonpolyposis Colorectal Cancer (Abe_2019). Co-occurrences with pathogenic variants have been reported in the literature in individuals affected with breast and ovarian cancer (BRCA1 c.3759_3760delTA, p.Lys1254GlufsX12; CHEK2 c.1283C>T, p.Ser428Phe) (Tung_2015) and also via internal testing (MSH6 c.2150_2153delTCAG, p.V717fsX18), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589175 SCV001469827 uncertain significance not provided 2019-09-18 criteria provided, single submitter clinical testing

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