7-5992000-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_000535.7(PMS2):c.961G>A(p.Val321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000357 in 1,598,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V321A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.961G>A | p.Val321Ile | missense_variant | 9/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.961G>A | p.Val321Ile | missense_variant | 9/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 152054Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251270Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135844
GnomAD4 exome AF: 0.0000353 AC: 51AN: 1446044Hom.: 0 Cov.: 27 AF XY: 0.0000319 AC XY: 23AN XY: 720456
GnomAD4 genome ? AF: 0.0000395 AC: 6AN: 152054Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74270
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with endometrial or colorectal cancer, some with tumors demonstrating isolated loss of PMS2 and/or microsatellite instability (Vaughn et al., 2010; Dudley et al., 2015; Wang et al., 2020); This variant is associated with the following publications: (PMID: 20205264, 25871621, 31391288, 31992580, 11574484) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2023 | The p.V321I variant (also known as c.961G>A), located in coding exon 9 of the PMS2 gene, results from a G to A substitution at nucleotide position 961. The valine at codon 321 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown pathogenicity in one individual from a cohort of 145 unrelated patient samples submitted for PMS2 whole gene analysis. Additionally, authors note that this individual's tumor exhibited isolated loss of PMS2 expression by immunohistochemistry (IHC) (Vaughn CP et al. Hum. Mutat. 2010 May;31:588-93). The alteration was also detected in the germline of a 54-year-old male diagnosed with two ascending colorectal cancers; both tumors exhibited isolated loss of PMS2 by IHC and high microsatellite instability (MSI-H), but this individual did not meet Amsterdam II criteria (Dudley B et al. Am. J. Surg. Pathol., 2015 Aug;39:1114-20). Additionally, this alteration was identified in an individual diagnosed with uterine cancer at 63. This individual's tumor exhibited loss of PMS2 expression by IHC (Wang Q et al. J Med Genet, 2020 07;57:487-499). 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 09, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 03, 2022 | Variant summary: PMS2 c.961G>A (p.Val321Ile) results in a conservative amino acid change located in the DNA mismatch repair protein family, N-terminal (IPR002099) of the encoded protein sequence. Four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251270 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer (4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.961G>A has been reported in the literature in affected individuals whose tumors exhibited isolated loss of PMS2 expression by immunohistochemistry without strong evidence for causality (Dudley_2015, Vaughn_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 321 of the PMS2 protein (p.Val321Ile). This variant is present in population databases (rs377043696, gnomAD 0.02%). This missense change has been observed in individual(s) with Lynch syndrome-associated cancer (PMID: 20205264, 25871621, 31992580). ClinVar contains an entry for this variant (Variation ID: 141713). 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. - |
Lynch syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at