ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1201G>C (p.Asp401His)

gnomAD frequency: 0.00001  dbSNP: rs1284362486
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000705206 SCV000834192 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 401 of the PMS2 protein (p.Asp401His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35449176). ClinVar contains an entry for this variant (Variation ID: 581395). 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 PMS2 protein function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health RCV000772183 SCV000905300 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-21 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with histidine at codon 401 of the PMS2 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 PMS2-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.
Ambry Genetics RCV000772183 SCV002650559 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-12 criteria provided, single submitter clinical testing The p.D401H variant (also known as c.1201G>C), located in coding exon 11 of the PMS2 gene, results from a G to C substitution at nucleotide position 1201. The aspartic acid at codon 401 is replaced by histidine, 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.

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