ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1715C>T (p.Ala572Val)

gnomAD frequency: 0.00001  dbSNP: rs770625733
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000167204 SCV000218041 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-23 criteria provided, single submitter clinical testing The p.A572V variant (also known as c.1715C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1715. The alanine at codon 572 is replaced by valine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). This alteration was reported in 1/450 patients diagnosed with colorectal cancer under the age of 50 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This alteration was also identified in a woman diagnosed with breast cancer before age 50 undergoing multigene panel testing (Tung N et al. Cancer. 2015 Jan;121:25-33). This amino acid position is poorly 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.
GeneDx RCV000679353 SCV000565418 uncertain significance not provided 2023-04-03 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with colorectal and other cancers (Tung et al., 2015; Yurgelun et al., 2015; Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 25980754, 27978560, 25186627)
Invitae RCV000537772 SCV000625553 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-09-25 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 572 of the PMS2 protein (p.Ala572Val). This variant is present in population databases (rs770625733, gnomAD 0.002%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754, 27978560). ClinVar contains an entry for this variant (Variation ID: 187471). 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. 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 RCV000167204 SCV000686156 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-10 criteria provided, single submitter clinical testing This missense variant replaces alanine with valine at codon 572 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 been reported in individuals affected with breast cancer (PMID: 25186627, 33471991), early onset colorectal cancer (PMID: 27978560), and suspected Lynch syndrome (PMID: 25980754). This variant has been identified in 2/251350 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.
Preventiongenetics, part of Exact Sciences RCV000679353 SCV000806187 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000167204 SCV002530222 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-01 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV002465554 SCV002760374 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002465554 SCV004241251 uncertain significance not specified 2023-12-18 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1715C>T (p.Ala572Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251350 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1715C>T has been reported in the literature in individuals affected with Colorectal Cancer or suspected of Lynch Syndrome (example: Pearlman_2017 and Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27978560, 25980754). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect, ClinGen RCV001824658 SCV002074900 not provided Lynch syndrome 4 no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 07-15-2020 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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