ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1937G>T (p.Arg646Met)

gnomAD frequency: 0.00006  dbSNP: rs372341850
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212864 SCV000149577 uncertain significance not provided 2022-10-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with uterine cancer and breast cancer (Yehia et al., 2018; Van Marcke et al., 2020); This variant is associated with the following publications: (PMID: 29684080, 32295625, 11292842)
Ambry Genetics RCV000115668 SCV000184619 likely benign Hereditary cancer-predisposing syndrome 2023-04-11 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV000195978 SCV000254609 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 646 of the PMS2 protein (p.Arg646Met). This variant is present in population databases (rs372341850, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and/or kidney cancer (PMID: 32295625, 32830346, 34326862). ClinVar contains an entry for this variant (Variation ID: 127768). 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 expected to disrupt PMS2 protein function with a positive 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 RCV000115668 SCV000691049 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-08 criteria provided, single submitter clinical testing This missense variant replaces arginine with methionine at codon 646 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 uterine cancer (PMID: 29684080), breast/ovarian cancer (PMID: 32295625, 34359559), prostate cancer (PMID: 31874108), as well as a healthy control individual in a large breast cancer case-control study (PMID: 33471991). This variant has been identified in 17/282520 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212864 SCV000889614 uncertain significance not provided 2020-12-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844040 SCV002103533 uncertain significance not specified 2023-09-18 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1937G>T (p.Arg646Met) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251116 control chromosomes (gnomAD), which is higher than the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Prostate Cancer phenotype (5e-05). However, due to this region having strong sequence similarity with PMS2 pseudogenes, this provides no conclusion about variant frequency with disease association. c.1937G>T has been reported in the literature in individuals affected with prostate-, breast- and renal carcinoma (Mateo_2020, VanMarcke_2020, Smith_2021), however it was also found in controls (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Prostate Cancer or 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: 33471991, 31874108, 32830346, 32295625). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5, Likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001844040 SCV002550700 uncertain significance not specified 2023-08-15 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000212864 SCV001553647 uncertain significance not provided no assertion criteria provided clinical testing The PMS2 p.Arg646Met variant was not identified in the literature. The variant was identified in dbSNP (rs372341850) as “with uncertain significance allele and ClinVar (classified as uncertain significance by Invitae, Color, Amgry Genetics and GeneDx). The variant was identified in control databases in 17 of 282,520 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 7208 chromosomes (freq: 0.0001), European in 16 of 129,092 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Arg646 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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