Submissions for variant NM_000179.3(MSH6):c.3303G>T (p.Lys1101Asn)

gnomAD frequency: 0.00003  dbSNP: rs370353868

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553191	SCV000624843	benign	Hereditary nonpolyposis colorectal neoplasms	2024-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001019819	SCV001181225	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-26	criteria provided, single submitter	clinical testing	The p.K1101N variant (also known as c.3303G>T), located in coding exon 5 of the MSH6 gene, results from a G to T substitution at nucleotide position 3303. The lysine at codon 1101 is replaced by asparagine, an amino acid with similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV001019819	SCV001353072	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 1101 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/31388 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.
CeGaT Center for Human Genetics Tuebingen	RCV001200628	SCV001371636	uncertain significance	not provided	2020-05-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806400	SCV005429406	uncertain significance	Lynch syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 1101 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 1/31388 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001019819	SCV005688847	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-27	criteria provided, single submitter	clinical testing	The missense variant NM_000179.3(MSH6):c.3303G>T (p.Lys1101Asn) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a moderate physicochemical difference between lysine and asparagine. The nucleotide c.3303 in MSH6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance