Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_000535.7(PMS2):āc.917T>Cā(p.Val306Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,578,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V306E) has been classified as Uncertain significance.
PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000535.7
PP3
MetaRNN computational evidence supports a deleterious effect, 0.892
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Apr 01, 2016
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. -
Uncertain significance, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Apr 18, 2022
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. -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
May 08, 2024
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 (PMID: 25186627, 25938944, 27443514); This variant is associated with the following publications: (PMID: 27443514, 28098136, 25186627, 25938944, 31883735, 11574484) -
Lynch syndrome 4 Uncertain:3
Uncertain significance, criteria provided, single submitter
clinical testing
Myriad Genetics, Inc.
Apr 04, 2023
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. -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Oct 26, 2017
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Baylor Genetics
Mar 13, 2024
- -
Lynch syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
Mendelics
Jul 02, 2018
- -
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Nov 20, 2023
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. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Dec 04, 2023
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. -
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Jan 05, 2023
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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Apr 21, 2017
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. -
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Jan 16, 2024
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. -