Submissions for variant NM_000535.7(PMS2):c.1399G>A (p.Val467Ile)

gnomAD frequency: 0.00008  dbSNP: rs373611083

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131574	SCV000186580	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-08	criteria provided, single submitter	clinical testing	The p.V467I variant (also known as c.1399G>A), located in coding exon 11 of the PMS2 gene, results from a G to A substitution at nucleotide position 1399. The valine at codon 467 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer (Nikitin AG et al. Front Oncol, 2020 May;10:666). This alteration was identified in an individual that had a personal and family history of colorectal cancer (Mounai Y et al. Case Rep Oncol, 2023 Jan;16:21-29). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457616	SCV000551955	benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000656947	SCV000565403	uncertain significance	not provided	2024-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 36743879, 32547938)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656947	SCV000601817	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131574	SCV000903129	likely benign	Hereditary cancer-predisposing syndrome	2015-11-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149908	SCV003837737	uncertain significance	Breast and/or ovarian cancer	2022-08-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998108	SCV004844225	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131574	SCV005045439	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055602	SCV005726087	uncertain significance	not specified	2024-11-21	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1399G>A (p.Val467Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251490 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PMS2 causing Lynch Syndrome (5.6e-05 vs 0.00011), allowing no conclusion about variant significance. c.1399G>A has been reported in the literature in individuals affected with Lynch Syndrome or Breast Cancer without strong evidence of causality (e.g. Nikitin_2020, Mounai_2023). These reports 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: 32547938, 36743879). ClinVar contains an entry for this variant (Variation ID: 142447). Based on the evidence outlined above, the variant was classified as uncertain significance.
Constitutional Genetics Lab, Leon Berard Cancer Center	RCV001249988	SCV001424002	uncertain significance	Lynch-like syndrome	2019-07-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000656947	SCV001551003	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Val332Ile variant was not identified in the literature nor was it identified in COGR, MutDB, LOVD 3.0, Insight Colon Cancer Gene Variant Database or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs373611083), ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics, and as likely benign by Color), and Cosmic (prostate, endometrium, large intestine and upper aerodigestive tract carcinomas). The variant was identified in control databases in 15 of 282874 chromosomes at a frequency of 0.00005303 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 5 of 24964 chromosomes (freq: 0.0002), East Asian in 3 of 19948 chromosomes (freq: 0.00015) and European (non-Finnish) in 7 of 129184 chromosomes (freq: 0.000054), but was not observed in the Latino, Ashkenazi Jewish, European (Finnish), Other, or South Asian populations. The p.Val332 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.
PreventionGenetics, part of Exact Sciences	RCV003894996	SCV004710356	uncertain significance	PMS2-related disorder	2024-02-07	no assertion criteria provided	clinical testing	The PMS2 c.1399G>A variant is predicted to result in the amino acid substitution p.Val467Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of African descent in gnomAD and is listed in ClinVar as uncertain by the majority of labs (https://www.ncbi.nlm.nih.gov/clinvar/variation/142447/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.