Submissions for variant NM_000535.7(PMS2):c.1243G>A (p.Val415Met)

gnomAD frequency: 0.00019  dbSNP: rs138387687

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131757	SCV000186800	likely benign	Hereditary cancer-predisposing syndrome	2019-04-29	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	RCV000198383	SCV000254596	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000586259	SCV000279138	likely benign	not provided	2021-06-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history of breast, ovarian, pancreatic, or other cancer (Lu 2015, Zhang 2015, Hu 2016, Yadav 2016, Cock-Rada 2017); This variant is associated with the following publications: (PMID: 22941189, 27846281, 26689913, 26483394, 26580448, 27878467, 28528518, 31433215, 31391288, 31422574, 31327751, 25567908)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855605	SCV000697289	likely benign	not specified	2023-08-31	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.1243G>A (p.Val415Met) 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 observed variant frequency is approximately 2.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. However, the variant is located in a region that is highly homologous to PMS2 pseudogene and the technology utilized for these datasets does not rule out pseudogene interference, therefore these data might not be reliable. c.1243G>A has been reported in the literature in sequencing studies of individuals affected with cancer including pancreatic cancer, acute megakaryoblastic leukemia, breast and/or ovarian cancer and colon cancer (e.g. Hu_2022, Guindalini_2022, Cock-Rada 2018, Hu 2016, Lu_2015, Okkels_2019, Yadav 2017, Zhang 2015). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 26483394, 26689913, 25567908, 27878467, 28528518, 26580448, 31422574, 31433215). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=5; likely benign, n=4; Benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV003323294	SCV000838180	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586259	SCV000888385	benign	not provided	2022-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131757	SCV000902659	likely benign	Hereditary cancer-predisposing syndrome	2016-03-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000987834	SCV001324212	uncertain significance	Lynch syndrome 4	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Sema4, Sema4	RCV000131757	SCV002529776	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000855605	SCV002550724	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000987834	SCV002584594	uncertain significance	Lynch syndrome 4	2022-08-30	criteria provided, single submitter	clinical testing	The PMS2 c.1243G>A (p.Val415Met) missense change has a maximum subpopulation frequency of 0.028% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with colorectal cancer and/or Lynch syndrome (PMID: 31433215). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355081	SCV001549853	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PMS2 p.Val415Met variant was identified in 3 of 456 proband chromosomes (frequency: 0.007) from individuals or families with lung adenocarcinoma, breast, ovarian or pancreatic cancer (Cock-Rada 2018, Drilon 2016, Hu 2016). The variant was also identified in dbSNP (ID: rs138387687 as "With Uncertain significance allele"), ClinVar (classified as likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America), and Cosmic (3x in lung, stomach or salivary gland). The variant was not identified in GeneInsight-COGR, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 44 of 277090 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24008 chromosomes (freq: 0.00004), Latino in 10 of 34418 chromosomes (freq: 0.0003), European in 32 of 126634 chromosomes (freq: 0.0003), and Finnish in 1 of 25792 chromosomes (freq: 0.00004), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Val415 residue is not conserved in mammals and 4 of 5 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 4 of 4 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535477	SCV001749408	not provided	Mismatch repair cancer syndrome 1; Lynch syndrome 4		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 06-15-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics, Academic Medical Center	RCV000586259	SCV001918329	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586259	SCV001975996	likely benign	not provided		no assertion criteria provided	clinical testing
Oncological Genetic Counseling Clinic, "Carlo Poma" Hospital	RCV002275085	SCV002562881	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-08-16	no assertion criteria provided	in vivo