7-5997374-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS1
The NM_001322011.2(PMS2):c.-179G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,606,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001322011.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000332 AC: 5AN: 150482Hom.: 0 Cov.: 29
GnomAD3 exomes AF: 0.0000719 AC: 18AN: 250288Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135276
GnomAD4 exome AF: 0.0000350 AC: 51AN: 1455614Hom.: 0 Cov.: 30 AF XY: 0.0000483 AC XY: 35AN XY: 724650
GnomAD4 genome AF: 0.0000332 AC: 5AN: 150598Hom.: 0 Cov.: 29 AF XY: 0.0000682 AC XY: 5AN XY: 73342
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:1
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Variant summary: PMS2 c.755G>A (p.Cys252Tyr) results in a non-conservative amino acid change located in the DNA mismatch repair protein, C-terminal domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250288 control chromosomes, predominantly at a frequency of 0.00053 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (7.1e-05). c.755G>A has been reported in the literature in one individual affected with Breast Cancer, co-occurring with a pathogenic variant of PMS2 (Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrences with other pathogenic variant(s) have been reported (PMS2 c.1908delA, p.Gln637fsX28), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 455741). Based on the evidence outlined above, the variant was classified as likely benign. -
Hereditary cancer-predisposing syndrome Benign:2
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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Lynch syndrome Uncertain:1
This missense variant replaces cysteine with tyrosine at codon 252 of the PMS2 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 18/250288 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. -
not provided Uncertain:1
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11574484, 34326862) -
Lynch syndrome 4;C5436817:Mismatch repair cancer syndrome 4 Uncertain:1
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Lynch syndrome 4 Uncertain:1
The missense variant in c.755G>A (p.Cys252Tyr) in PMS2 gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. The p.Cys252Tyr variant is reported with the allele frequency of 0.007192% in gnomAD Exome and is novel (not in any individuals) in 1000 Genomes. The amino acid Cys at position 252 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Cys252Tyr in PMS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at