Submissions for variant NM_000535.7(PMS2):c.935T>C (p.Met312Thr)

dbSNP: rs530021751

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081365	SCV000253303	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000588576	SCV000572445	uncertain significance	not provided	2023-08-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with breast cancer (Tung et al., 2016); This variant is associated with the following publications: (PMID: 11574484, 26976419)
Ambry Genetics	RCV000563510	SCV000663443	likely benign	Hereditary cancer-predisposing syndrome	2023-03-06	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479057	SCV000697402	uncertain significance	not specified	2023-11-08	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.935T>C (p.Met312Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251298 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05), strongly suggesting that the variant is benign, however presence of a pseudogene has also been observed in the ExAC population. c.935T>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=3) and VUS (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000563510	SCV000910993	likely benign	Hereditary cancer-predisposing syndrome	2017-06-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000588576	SCV003811209	uncertain significance	not provided	2022-05-16	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357920	SCV001553521	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The PMS2 p.Met312Thr variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Tung_20016_26976419). The variant was also identified in dbSNP (ID: rs530021751) “With Uncertain significance allele”, ClinVar (classified likely benign by Invitae and uncertain significance by GeneDx), Clinvitae (2x), and in control databases in 30 (1 homozygous) of 246124 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 3 of 5482 chromosomes (freq: 0.0005) and South Asian in 27 (1 homozygous) of 30780 chromosomes (freq: 0.0009); it was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian and European Finnish populations. The variant was not found in the COGR, Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified by our laboratory in 1 individual with CRC at 28 years of age, co-occurring with a pathogenic MLH1 variant (c.1219C>T, p.Gln407X). The p.Met312 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of Thr 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, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely benign.