ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.643G>A (p.Val215Ile) (rs145959653)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000197162 SCV000254332 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-30 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 215 of the MSH6 protein (p.Val215Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs145959653, ExAC 0.02%). This variant has been observed in individual(s) with endometrial cancer (PMID: 23104009). ClinVar contains an entry for this variant (Variation ID: 216321). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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.
Ambry Genetics RCV000220344 SCV000276053 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-10 criteria provided, single submitter clinical testing The p.V215I variant (also known as c.643G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. 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.
Counsyl RCV000663025 SCV000786051 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-02-16 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761118 SCV000891034 uncertain significance Lynch syndrome 2020-10-15 criteria provided, single submitter clinical testing The MSH6 c.643G>A (p.Val215Ile) missense change has a maximal subpopulation frequency of 0.025% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-48025765-G-A). Five of six in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. This variant has been reported in an individual with colorectal adenoma (PMID: 29245953). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4.
Color Health, Inc RCV000220344 SCV000903133 likely benign Hereditary cancer-predisposing syndrome 2016-01-07 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000582427 SCV000691918 uncertain significance not specified no assertion criteria provided clinical testing

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