Submissions for variant NM_000535.7(PMS2):c.2386G>A (p.Val796Ile)

gnomAD frequency: 0.00001  dbSNP: rs368737800

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212872	SCV000149594	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed with PMS2 p.(N575D) in individuals with breast cancer, colon cancer, or other Lynch syndrome-related cancer and/or polyps (Yurgelun et al., 2015; Tung et al., 2016; Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 27978560, 26976419, 25980754, Fukui2011[Chapter])
Ambry Genetics	RCV000115685	SCV000186210	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-13	criteria provided, single submitter	clinical testing	The p.V796I variant (also known as c.2386G>A), located in coding exon 14 of the PMS2 gene, results from a G to A substitution at nucleotide position 2386. The valine at codon 796 is replaced by isoleucine, an amino acid with highly similar properties. This variant was detected in a cohort of 1260 individuals with a Lynch syndrome-related tumor and/or colon polyps who underwent a multigene hereditary cancer panel (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20) and was reported in a woman with MMR-proficient right-sided colon cancer diagnosed at age 48 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). This alteration has also been reported in a cohort of 488 patients with stages I to III breast cancer diagnosed over age 50 who were tested with a 25-gene panel test (Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). This amino acid position is 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	RCV000465421	SCV000551956	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 796 of the PMS2 protein (p.Val796Ile). 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 clinical features of Lynch syndrome or breast cancer (PMID: 25980754, 26976419). ClinVar contains an entry for this variant (Variation ID: 127781). 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 not expected to disrupt PMS2 protein function with a negative 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798335	SCV002042803	uncertain significance	Breast and/or ovarian cancer	2022-08-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330440	SCV004039149	uncertain significance	not specified	2023-08-14	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.2386G>A (p.Val796Ile) results in a conservative amino acid change located in the MutL C-terminal dimerisation domain (IPR014790) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 245522 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2386G>A has been reported in the literature with another VUS variant PMS2: c.1723A>G (p.Asn575Asp) in individuals affected with Lynch Syndrome or early-onset colorectal cancer without strong evidence for causality (example, Tung_2016, Yurgelun_2015, Pearlman_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. 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: 27978560, 26976419, 25980754). Four 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.
Baylor Genetics	RCV003460826	SCV004205443	uncertain significance	Lynch syndrome 4	2023-09-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115685	SCV004358997	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 796 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 identified in an individual affected with early onset colorectal cancer whose tumor demonstrated mismatch repair proficiency (PMID: 27978560), as well as individuals affected with breast cancer (PMID: 26976419) and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 5/245522 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	RCV000212872	SCV001550182	uncertain significance	not provided		no assertion criteria provided	clinical testing	The PMS2 p.Val796Ile variant was identified in 3 of 4396 proband chromosomes (frequency: 0.0007) from individuals or families with lynch syndrome, colon, or breast cancer (Pearlman 2017, Tung 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs368737800) as "With Uncertain significance allele ", and in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 4 of 240828 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 4 of 108128 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Val796 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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.