Submissions for variant NM_000179.3(MSH6):c.67G>C (p.Ala23Pro)

gnomAD frequency: 0.00001  dbSNP: rs730881810

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482378	SCV000566690	uncertain significance	not provided	2023-12-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000537973	SCV000624992	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-08-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565704	SCV000669924	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-24	criteria provided, single submitter	clinical testing	The p.A23P variant (also known as c.67G>C), located in coding exon 1 of the MSH6 gene, results from a G to C substitution at nucleotide position 67. The alanine at codon 23 is replaced by proline, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	RCV000565704	SCV000903628	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 23 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 3/274242 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.
Sema4, Sema4	RCV000565704	SCV002536346	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004002285	SCV004832332	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with proline at codon 23 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 3/274242 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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003387854	SCV004099446	uncertain significance	Lynch syndrome 5	2023-10-30	no assertion criteria provided	clinical testing