Submissions for variant NM_000535.7(PMS2):c.917T>C (p.Val306Ala)

gnomAD frequency: 0.00003  dbSNP: rs786201878

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164381	SCV000215016	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-05	criteria provided, single submitter	clinical testing	The p.V306A variant (also known as c.917T>C), located in coding exon 9 of the PMS2 gene, results from a T to C substitution at nucleotide position 917. The valine at codon 306 is replaced by alanine, an amino acid with similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 11;29:1381-1389). In a study of 51 individuals with multiple colonic adenomas from 48 families who underwent whole-exome sequencing, this variant was identified in one patient with 50 polyps (Weren RD et al. Nat Genet, 2015 Jun;47:668-71). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000588443	SCV000279297	uncertain significance	not provided	2023-06-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer, endometrial cancer, and polyps (Tung et al., 2015; Weren et al., 2015; Ring et al., 2016); This variant is associated with the following publications: (PMID: 27443514, 28098136, 25186627, 25938944, 31883735, 11574484)
Invitae	RCV000470824	SCV000551971	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 306 of the PMS2 protein (p.Val306Ala). This variant is present in population databases (rs786201878, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer, colorectal adenomas, and/or endometrial cancer (PMID: 25186627, 25938944, 27443514). ClinVar contains an entry for this variant (Variation ID: 185028). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588443	SCV000697399	uncertain significance	not provided	2016-04-01	criteria provided, single submitter	clinical testing	Variant summary: The PMS2 c.917T>C variant affects a conserved nucleotide, resulting in amino acid change from Val to Ala. 4/4 in-silico tools predict damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was not found in 119904 control chromosomes. It has been cited in one patient that had polyps and a first degree relative with CRC or polyposis, but co-segregation was not determined (Weren_NG_2015). In addition, one clinical laboratory classified this variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213750	SCV000731463	uncertain significance	not specified	2017-04-21	criteria provided, single submitter	clinical testing	The p.Val306Ala variant in PMS2 has been reported in 1 individual with endometri al cancer (Ring 2016), and has also been reported in ClinVar (Variation ID 18502 8). This variant was absent from large population studies. Computational predict ion tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Val306 Ala variant is uncertain.
Counsyl	RCV000662825	SCV000785670	uncertain significance	Lynch syndrome 4	2017-10-26	criteria provided, single submitter	clinical testing
Mendelics	RCV000708990	SCV000838186	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164381	SCV000909665	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 306 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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), endometrial cancer (PMID: 27443514) and colorectal cancer with microsatellite stability (PMID: 25938944). This variant has been identified in 2/251190 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588443	SCV003800132	uncertain significance	not provided	2022-04-18	criteria provided, single submitter	clinical testing	The PMS2 c.917T>C; p.Val306Ala variant (rs786201878) has been reported in the literature in individuals with colorectal adenomas, breast, or endometrial cancer, but the variant was not determined to be causative (Ring 2016, Tung 2015, Weren 2015). This variant is reported in ClinVar (Variation ID: 185028) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The valine at codon 306 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.824). Due to limited information, the clinical significance of the p.Val306Ala variant is uncertain at this time. References: Ring KL et al. Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod Pathol. 2016 Nov;29(11):1381-1389. PMID: 27443514. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Weren RD et al. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015 Jun;47(6):668-71. PMID: 25938944.
Myriad Genetics, Inc.	RCV000662825	SCV004019801	uncertain significance	Lynch syndrome 4	2023-04-04	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000662825	SCV004205454	uncertain significance	Lynch syndrome 4	2023-09-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708990	SCV004839883	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 306 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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), endometrial cancer (PMID 27443514) and colorectal cancer with microsatellite stability (PMID: 25938944). This variant has been identified in 2/251190 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.