ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2302C>G (p.Pro768Ala)

dbSNP: rs35946687
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481556 SCV000570726 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2302C>G at the cDNA level, p.Pro768Ala (P768A) at the protein level, and results in the change of a Proline to an Alanine (CCT>GCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Pro768Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Alanine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Pro768Ala occurs at a position that is not conserved and is located within MutS domain III (Terui 2013). 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 Pro768Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000822224 SCV000963016 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-08 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001190572 SCV001358086 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 768 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 been identified in 1/251152 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 RCV001190572 SCV002734108 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-20 criteria provided, single submitter clinical testing The p.P768A variant (also known as c.2302C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2302. The proline at codon 768 is replaced by alanine, an amino acid with highly 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.
Baylor Genetics RCV003470572 SCV004195623 uncertain significance Endometrial carcinoma 2023-08-02 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004003355 SCV004842027 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces proline with alanine at codon 768 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 been identified in 1/251152 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.

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