Submissions for variant NM_000535.7(PMS2):c.962T>C (p.Val321Ala)

gnomAD frequency: 0.00001  dbSNP: rs186448384

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000206591	SCV000259945	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-28	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 321 of the PMS2 protein (p.Val321Ala). This variant is present in population databases (rs186448384, gnomAD 0.04%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 30521064). ClinVar contains an entry for this variant (Variation ID: 219846). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PMS2 protein function. 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.
Ambry Genetics	RCV000213107	SCV000274557	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-05	criteria provided, single submitter	clinical testing	The p.V321A variant (also known as c.962T>C), located in coding exon 9 of the PMS2 gene, results from a T to C substitution at nucleotide position 962. The valine at codon 321 is replaced by alanine, an amino acid with similar properties. This alteration was identified in a 61 year old male with colorectal cancer demonstrating loss of MLH1 and PMS2 proteins by IHC whose family history did not meet Amsterdam criteria II (Jiang W et al. Int J Cancer, 2019 05;144:2161-2168). This alteration was also identified in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Kwong A et al. J Mol Diagn, 2020 Apr;22:544-554; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000213107	SCV000686261	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 321 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 two individuals affected with colorectal cancer, one whose tumor displayed PMS2 protein loss via immunohistochemistry analysis and the other whose tumor displayed PMS2 and MLH1 protein loss with no MLH1 methylation detected (PMID: 30521064). The variant has also been observe in individuals with either personal or family history of breast and/or ovarian cancer (PMID: 31742824, 32068069). This variant has been identified in 9/282634 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328038	SCV000697405	uncertain significance	not specified	2021-02-26	criteria provided, single submitter	clinical testing	Variant summary: PMS2 c.962T>C (p.Val321Ala) results in a non-conservative amino acid change located in the DNA mismatch repair protein family, N-terminal domain and DNA mismatch repair protein, S5 domain 2-like domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251268 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.962T>C has been reported in the literature in individuals affected with colorectal cancer, familial adenomatous polyposis, breast and/or ovarian cancer (Jiang_2019, Kim_2019, Shao_2019, Kwong_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. One co-occurrence with another pathogenic variant has been reported (APC c.3927_3931del, p.Glu1309AspfsTer4, Kim_2019), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl	RCV000662446	SCV000784914	uncertain significance	Lynch syndrome 4	2017-02-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000588695	SCV000806229	uncertain significance	not provided	2017-06-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000588695	SCV002008760	uncertain significance	not provided	2022-06-20	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 colorectal cancer whose tumor demonstrated absence of MLH1 and PMS2 on immunohistochemistry as well as individuals with a personal or family history of breast or ovarian cancer (Jiang 2019, Kwong 2020, Shao 2020); This variant is associated with the following publications: (PMID: 32661327, 31742824, 32068069, 11574484, 30521064, 31269945)
Fulgent Genetics, Fulgent Genetics	RCV002485340	SCV002779203	uncertain significance	Lynch syndrome 4; Mismatch repair cancer syndrome 4	2022-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662446	SCV004019802	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	RCV000662446	SCV004205361	uncertain significance	Lynch syndrome 4	2023-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997584	SCV004839872	uncertain significance	Lynch syndrome	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 321 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 two individuals affected with colorectal cancer, one whose tumor displayed PMS2 protein loss via immunohistochemistry analysis and the other whose tumor displayed PMS2 and MLH1 protein loss with no MLH1 methylation detected (PMID: 30521064). The variant has also been observe in individuals with either personal or family history of breast and/or ovarian cancer (PMID: 31742824, 32068069). This variant has been identified in 9/282634 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.
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093690	SCV001250874	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153482	SCV003843698	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing