ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3887A>G (p.Lys1296Arg)

dbSNP: rs1553333526
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000580786 SCV000685458 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-05 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 1296 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 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000805168 SCV000945115 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1296 of the MSH6 protein (p.Lys1296Arg). 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: 490013). 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 RCV000580786 SCV002620578 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-17 criteria provided, single submitter clinical testing The c.3887A>G (p.K1296R) alteration is located in exon 9 (coding exon 9) of the MSH6 gene. This alteration results from a A to G substitution at nucleotide position 3887, causing the lysine (K) at amino acid position 1296 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV004568267 SCV005054998 uncertain significance Endometrial carcinoma 2023-12-15 criteria provided, single submitter clinical testing

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