Submissions for variant NM_000179.3(MSH6):c.158C>A (p.Ala53Asp)

dbSNP: rs1553408288

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000564219	SCV000669898	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-06	criteria provided, single submitter	clinical testing	The p.A53D variant (also known as c.158C>A), located in coding exon 1 of the MSH6 gene, results from a C to A substitution at nucleotide position 158. The alanine at codon 53 is replaced by aspartic acid, an amino acid with dissimilar properties. In a study of 63 cases of non-medullary thyroid cancer, this alteration was identified in one proband with sporadic papillary thyroid cancer who also carried an insertion in MSH6 (designated G56GPR). Both alterations were deemed likely benign, based on in silico predictions (Yu Y et al. Sci Rep, 2015 Nov;5:16129). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001349167	SCV001543497	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 53 of the MSH6 protein (p.Ala53Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with non-medullary thyroid, breast, or pancreatic cancer (PMID: 26530882, 35171259, 35449176). ClinVar contains an entry for this variant (Variation ID: 483762). 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.
All of Us Research Program, National Institutes of Health	RCV004001046	SCV004828108	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with aspartic acid at codon 53 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 an individual affected with non-medullary thyroid cancer (PMID: 26530882). 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.
Baylor Genetics	RCV004569220	SCV005054977	uncertain significance	Endometrial carcinoma	2024-01-05	criteria provided, single submitter	clinical testing