Submissions for variant NM_000535.7(PMS2):c.2174C>T (p.Ala725Val)

gnomAD frequency: 0.00002  dbSNP: rs150630090

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164743	SCV000215415	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-14	criteria provided, single submitter	clinical testing	The p.A725V variant (also known as c.2174C>T), located in coding exon 12 of the PMS2 gene, results from a C to T substitution at nucleotide position 2174. The alanine at codon 725 is replaced by valine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20) and 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 not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000206423	SCV000260118	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 725 of the PMS2 protein (p.Ala725Val). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This missense change has been observed in individual(s) with breast cancer and/or clinical features of Lynch syndrome (PMID: 25186627, 25980754). ClinVar contains an entry for this variant (Variation ID: 185339). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Counsyl	RCV000410095	SCV000488728	uncertain significance	Lynch syndrome 4	2016-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000486892	SCV000565827	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer or a Lynch syndrome-associated tumor (Tung et al., 2015; Yurgelun et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 25186627, 27203213, Fukui2011[Chapter])
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761045	SCV000890960	uncertain significance	Lynch syndrome	2020-10-22	criteria provided, single submitter	clinical testing	The PMS2 c.2174C>T (p.Ala725Val) missense change has a maximum subpopulation frequency of 0.0067% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/7-6022455-G-A). Six of six in silico tools predict a benign effect of this variant on protein function (BP4). This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceAI, MaxEntScan) do not predict a difference in splicing. To our knowledge, functional studies have not been performed to confirm these predictions. This variant has been reported in an individual with suspected Lynch syndrome (PMID: 25980754) and an individual with familial breast cancer (PMID: 25186627). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781746	SCV000920035	uncertain significance	not specified	2023-09-03	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2174C>T (p.Ala725Val) results in a non-conservative amino acid change located in the MutL, C-terminal, dimerisation (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 244484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2174C>T has been reported in the literature as a VUS in settings of multigene cancer panel testing (example, Yurgelun_2015, Tung_2014, Margolskee_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cance/Lynch syndromer. At-least one co-occurrence with another pathogenic variant(s) has been reported (Tung_2014, BRCA2 c.8167G>C, p.Asp2723His), providing supporting evidence for a benign role. 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: 27203213, 25980754, 25186627). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000410095	SCV004019819	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486892	SCV004218979	uncertain significance	not provided	2023-05-01	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000012 (3/244484 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with clinical features of Lynch syndrome (PMID: 25980754 (2015)) and in an individual with breast cancer (PMID: 25186627 (2015)). In addition, this variant has been reported in the somatic state in an individual with hepatosplenic T-cell lymphoma (PMID: 27203213 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000164743	SCV004359039	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 725 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with a Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754) or breast cancer (PMID: 25186627). This variant has been identified in 3/244484 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358129	SCV001553785	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PMS2 p.Ala725Val variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). The variant was also identified in dbSNP (ID: rs150630090) as "With Uncertain significance allele", and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and three other submitters). The variant was identified in control databases in 3 of 239296 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 1 of 108138 chromosomes (freq: 0.000009), and South Asian in 2 of 30240 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Ala725 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 p.Ala725Val variant occurs in the last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, 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.