ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3259C>G (p.Pro1087Ala) (rs63750998)

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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 RCV000128933 SCV000172804 likely benign Hereditary cancer-predisposing syndrome 2017-08-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Color RCV000128933 SCV000902770 likely benign Hereditary cancer-predisposing syndrome 2016-05-24 criteria provided, single submitter clinical testing
Counsyl RCV000411062 SCV000487890 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000587527 SCV000211318 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3259C>G at the cDNA level, p.Pro1087Ala (P1087A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). This variant has been observed in at least one individual with colorectal cancer, one with ovarian cancer, and one with breast cancer (Pal 2012, Chubb 2015, Yehia 2018). Loss of heterozygosity (LOH) was observed at this position in an endometrial carcinoma and a breast adenocarcinoma and, in both cases, the variant was confirmed as present in the patient's germline (Lu 2015). MSH6 Pro1087Ala was observed at an allele frequency of 0.02% (44/24,038) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Pro1087Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587527 SCV000695850 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3259C>G (p.Pro1087Ala) variant located in the DNA mismatch repair protein MutS core domain (via InterPro) causes a missense change involving a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 10/121366 (1/12135), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Multiple publications have cited the variant in affected individuals (CrC and BrC), however, co-occurrence and cosegregation data was not provided. In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000122963 SCV000166228 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 1087 of the MSH6 protein (p.Pro1087Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs63750998, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with ovarian cancer (PMID: 23047549) and colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 135841). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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.

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