Submissions for variant NM_000179.3(MSH6):c.743G>C (p.Arg248Pro)

dbSNP: rs764870249

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000476123	SCV000551256	benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000587170	SCV000568152	uncertain significance	not provided	2023-10-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754); This variant is associated with the following publications: (PMID: 21437237, 25980754)
Ambry Genetics	RCV000562563	SCV000662396	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-22	criteria provided, single submitter	clinical testing	The p.R248P variant (also known as c.743G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 743. The arginine at codon 248 is replaced by proline, an amino acid with dissimilar properties. This alteration was reported in one individual from a cohort of 1260 individuals undergoing clinical Lynch syndrome testing via a multigene panel (Yurgelun MB et al. Gastroenterology. 2015 May 13). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824790	SCV000695927	uncertain significance	not specified	2022-01-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.743G>C (p.Arg248Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251102 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.743G>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with colorectal cancer (example, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000562563	SCV000908358	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 248 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 an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 2/251102 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.
Sema4, Sema4	RCV000562563	SCV002536354	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	curation
Baylor Genetics	RCV003463941	SCV004197662	uncertain significance	Endometrial carcinoma	2023-10-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004001853	SCV004836963	uncertain significance	Lynch syndrome	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with proline at codon 248 of the MSH6 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has also been identified in 2/251102 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.