Submissions for variant NM_000179.3(MSH6):c.3819T>G (p.Asn1273Lys)

gnomAD frequency: 0.00001  dbSNP: rs759642651

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000538478	SCV000624926	benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-05	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774615	SCV000908435	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1273 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251052 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.
Ambry Genetics	RCV000774615	SCV001182811	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-07	criteria provided, single submitter	clinical testing	The p.N1273K variant (also known as c.3819T>G), located in coding exon 9 of the MSH6 gene, results from a T to G substitution at nucleotide position 3819. The asparagine at codon 1273 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly 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.
GeneDx	RCV002264952	SCV002546614	uncertain significance	not provided	2022-07-07	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 an individual with premature ovarian insufficiency and unspecified cancer history (Tang et al., 2020); This variant is associated with the following publications: (PMID: 17531815, 21120944, 32789750)
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153677	SCV003843670	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing