Submissions for variant NM_000179.3(MSH6):c.3904G>A (p.Ala1302Thr)

dbSNP: rs1553333561

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542091	SCV000624942	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-26	criteria provided, single submitter	clinical testing	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. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1302 of the MSH6 protein (p.Ala1302Thr). This variant is not present in population databases (gnomAD no frequency). 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: 455306). 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	RCV000574694	SCV000676124	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-07	criteria provided, single submitter	clinical testing	The p.A1302T variant (also known as c.3904G>A), located in coding exon 9 of the MSH6 gene, results from a G to A substitution at nucleotide position 3904. The alanine at codon 1302 is replaced by threonine, 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.
Color Diagnostics, LLC DBA Color Health	RCV000574694	SCV000685460	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1302 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 not been reported in individuals affected with hereditary cancer in the literature. 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	RCV000708895	SCV000837924	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470706	SCV004197706	uncertain significance	Endometrial carcinoma	2023-09-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708895	SCV004835164	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1302 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 not been reported in individuals affected with hereditary cancer in the literature. 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.