7-5991999-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_000535.7(PMS2):c.962T>C(p.Val321Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000939 in 1,597,510 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152186Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251268Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
GnomAD4 exome AF: 0.00000830 AC: 12AN: 1445206Hom.: 0 Cov.: 27 AF XY: 0.00000278 AC XY: 2AN XY: 720132
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152304Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3AN XY: 74458
ClinVar
Submissions by phenotype
Lynch syndrome 4 Uncertain:3
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. -
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not provided Uncertain:2
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) -
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Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Uncertain:2
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Hereditary cancer-predisposing syndrome Uncertain:2
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 observed 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. -
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. -
Ovarian cancer Pathogenic:1
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not specified Uncertain:1
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. -
Lynch syndrome 1 Uncertain:1
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Lynch syndrome Uncertain:1
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. -
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
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 PMS2-related conditions (PMID: 30521064, 34897210, 35449176, 36243179). ClinVar contains an entry for this variant (Variation ID: 219846). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt PMS2 function with a negative predictive value of 95%. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at