Submissions for variant NM_000179.3(MSH6):c.3742C>T (p.His1248Tyr)

gnomAD frequency: 0.00001  dbSNP: rs63750882

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220341	SCV000274985	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-23	criteria provided, single submitter	clinical testing	The p.H1248Y variant (also known as c.3742C>T), located in coding exon 8 of the MSH6 gene, results from a C to T substitution at nucleotide position 3742. The histidine at codon 1248 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000552496	SCV000624909	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1248 of the MSH6 protein (p.His1248Tyr). This variant is present in population databases (rs63750882, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 231211). 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 expected to disrupt MSH6 protein function with a positive 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.
Color Diagnostics, LLC DBA Color Health	RCV000220341	SCV000685440	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 1248 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 uterine cancer (PMID: 29684080). This variant has been identified in 1/251182 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.
GeneDx	RCV001775683	SCV002013849	uncertain significance	not provided	2021-11-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with endometrial cancer (Yehia 2018); This variant is associated with the following publications: (PMID: 17531815, 21120944, 29684080)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224227	SCV003920217	uncertain significance	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2022-07-07	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in association with disease. This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.002% [1/41470]; https://gnomad.broadinstitute.org/variant/2-47806299-C-T?dataset=gnomad_r3) and in ClinVar, with multiple laboratories classifying it as of uncertain significance (Variation ID:231211). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. A different variant at the same amino acid position (p.His1248Asp) has been reported in association with suspected Lynch syndrome and was found to be damaging to the protein in an in silico functional study (Berends 2002 PMID:11709755; Cyr 2008 PMID:18790734). In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
All of Us Research Program, National Institutes of Health	RCV003997889	SCV004835123	uncertain significance	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing