ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2941A>G (p.Ile981Val)

dbSNP: rs730881799
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160684 SCV000211305 uncertain significance not provided 2023-10-20 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in two affected individuals from a family meeting Amsterdam criteria as well as an individual with breast cancer (Liccardo et al., 2017; Paduano et al., 2022); This variant is associated with the following publications: (PMID: 31391288, 17531815, 21120944, 35886069, 28481244)
Labcorp Genetics (formerly Invitae), Labcorp RCV000469541 SCV000551235 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-07 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 981 of the MSH6 protein (p.Ile981Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome and/or MSH6-related conditions (PMID: 28481244, 35886069). ClinVar contains an entry for this variant (Variation ID: 182638). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. 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 RCV000565911 SCV000673922 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-27 criteria provided, single submitter clinical testing The p.I981V variant (also known as c.2941A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2941. The isoleucine at codon 981 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in two siblings diagnosed with colorectal cancer at ages 42 and 57, respectively, from a family meeting Amsterdam criteria (Liccardo R et al. Int J Mol Sci, 2017 May;18:). This amino acid position is not well 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.
Color Diagnostics, LLC DBA Color Health RCV000565911 SCV000904023 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-08 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 981 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals with Lynch syndrome from a family that met the Amsterdam criteria (PMID: 28481244), and in an individual affected with breast cancer (PMID: 35886069). This variant has not been identified 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.
Mendelics RCV002247557 SCV002518281 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000565911 SCV002535778 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-22 criteria provided, single submitter curation
Baylor Genetics RCV003462095 SCV004195690 uncertain significance Endometrial carcinoma 2023-06-30 criteria provided, single submitter clinical testing

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