Submissions for variant NM_000179.3(MSH6):c.1602C>G (p.Asn534Lys)

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Total submissions: 7

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679216	SCV000618398	uncertain significance	not provided	2017-04-10	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1602C>G at the cDNA level, p.Asn534Lys (N534K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asn534Lys was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asn534Lys occurs at a position that is not conserved and is located in the connector domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Asn534Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000533328	SCV000624669	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 534 of the MSH6 protein (p.Asn534Lys). 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: 449925). 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.
Ambry Genetics	RCV000575962	SCV000669946	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-02	criteria provided, single submitter	clinical testing	The p.N534K variant (also known as c.1602C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 1602. The asparagine at codon 534 is replaced by lysine, an amino acid with 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.
PreventionGenetics, part of Exact Sciences	RCV000679216	SCV000805847	uncertain significance	not provided	2017-03-09	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761146	SCV000891062	uncertain significance	Lynch syndrome	2020-10-15	criteria provided, single submitter	clinical testing	The MSH6 c.1602C>G (p.Asn534Lys) missense change is absent in gnomAD v2.1.1 (PM2_Supporting, https://gnomad.broadinstitute.org/). Six of seven in silico tools predict a benign effect of this variant on protein function (BP4), but these predictions have not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or CMMRD. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4.
Color Diagnostics, LLC DBA Color Health	RCV000575962	SCV000911934	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 534 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 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	RCV003464112	SCV004195811	uncertain significance	Endometrial carcinoma	2023-05-01	criteria provided, single submitter	clinical testing

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