ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1049C>T (p.Ala350Val) (rs587782331)

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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 RCV000131253 SCV000186215 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing The p.A350V variant (also known as c.1049C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1049. The alanine at codon 350 is replaced by valine, an amino acid with similar properties. This alteration has been observed to be linked in cis with the MSH6 alteration, p.G566R,​ and this haplotype has been identified in many individuals who do not have a personal or family history that is consistent with or suggestive of HNPCC/Lynch syndrome (Ambry internal data). This haplotype has also been identified in a homozygous state in an individual without characteristics of CMMRD (Ambry internal data). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000168415 SCV000211269 likely benign not provided 2020-02-19 criteria provided, single submitter clinical testing
Invitae RCV001086248 SCV000219109 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131253 SCV000902914 benign Hereditary cancer-predisposing syndrome 2017-01-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000168415 SCV001134385 likely benign not provided 2019-08-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212642 SCV001519616 benign not specified 2021-03-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1049C>T (p.Ala350Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 251258 control chromosomes. The observed variant frequency is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1049C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. A recent report evaluating a tumor characteristic likelihood ratio (TCLR) in combination with a multifactorial variant prediction (MVP) model predicted this variant to have a benign outcome (Li_2020). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=2; likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.

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