7-5982897-G-A
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000535.7(PMS2):c.2101C>T(p.His701Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. H701P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.2101C>T | p.His701Tyr | missense_variant | 12/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.2101C>T | p.His701Tyr | missense_variant | 12/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes Cov.: 30
GnomAD3 exomes AF: 0.00000451 AC: 1AN: 221718Hom.: 0 AF XY: 0.00000829 AC XY: 1AN XY: 120666
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 30
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2023 | The p.H701Y variant (also known as c.2101C>T), located in coding exon 12 of the PMS2 gene, results from a C to T substitution at nucleotide position 2101. The histidine at codon 701 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in a proband with MSI-H colorectal cancer and has also been identified as somatic in conjunction with copy neutral loss of heterozygosity (CN-LOH) in a MSI-H endometrial tumor with isolated loss of PMS2 protein expression by immunohistochemistry (IHC) (Ambry internal data). Based on internal structural analysis, this variant sits at the interface between PMS2/MutLa and is anticipated to result in a significant decrease in structural stability (Gueneau E et al. Nat Struct Mol Biol, 2013 Apr;20:461-8; Ambry internal data). Another alteration at the same codon, p.H701R (c.2102A>G), was also determined to be structurally destabilizing and was detected in a proband whose MSI-H colon cancer demonstrated isolated loss of PMS2 protein expression by IHC (Ambry internal data). Furthermore, the proband had a strong family history of HNPCC/Lynch syndrome-related cancers (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 05, 2022 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 701 of the PMS2 protein (p.His701Tyr). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt PMS2 protein function. ClinVar contains an entry for this variant (Variation ID: 411077). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. 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. - |
Lynch syndrome 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at