Submissions for variant NM_000179.3(MSH6):c.3163G>C (p.Ala1055Pro)

dbSNP: rs587779254

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000114751	SCV000148649	likely pathogenic	Lynch syndrome	2018-12-19	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability >0.95
Ambry Genetics	RCV000223291	SCV000277857	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-25	criteria provided, single submitter	clinical testing	The p.A1055P variant (also known as c.3163G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 3163. The alanine at codon 1055 is replaced by proline, an amino acid with highly similar properties. This variant has been observed in an individual whose Lynch-related tumor demonstrated loss of MSH6 expression on immunohistochemistry (IHC); however, this variant has also been observed in an individual whose Lynch-related tumor was microsatellite stable (MSS) (Ambry internal data). A1055P demonstrated deficient protein function in an in vitro complementation assay compared to wild type MSH6 (Drost M et al. Genet. Med., 2020 May;22:847-856). Based on internal structural analysis using published crystal structures, this alteration destabilizes the structure of MSH6 in the lever domain (Warren JJ et al. Mol Cell, 2007 May;26:579-92). 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.
Color Diagnostics, LLC DBA Color Health	RCV000223291	SCV000685356	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 1055 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). Functional studies have shown that this variant has 5.5% of wildtype mismatch repair activity in vitro (PMID: 31965077). This variant has been reported in individuals affected with Lynch syndrome or Lynch syndrome-associated cancer (PMID: 25559809; ClinVar SCV000277857.7, SCV001388045.4; LOVD database). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Invitae	RCV001216258	SCV001388045	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1055 of the MSH6 protein (p.Ala1055Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 126892). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. Experimental studies have shown that this missense change affects MSH6 function (PMID: 31965077). 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.
Myriad Genetics, Inc.	RCV003453034	SCV004185571	likely pathogenic	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad internal data].