2-189795860-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000534.5(PMS1):c.224C>T(p.Thr75Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,612,500 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000534.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000605 AC: 92AN: 152076Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000613 AC: 154AN: 251426Hom.: 0 AF XY: 0.000670 AC XY: 91AN XY: 135888
GnomAD4 exome AF: 0.00136 AC: 1991AN: 1460306Hom.: 3 Cov.: 30 AF XY: 0.00130 AC XY: 943AN XY: 726558
GnomAD4 genome AF: 0.000604 AC: 92AN: 152194Hom.: 1 Cov.: 32 AF XY: 0.000591 AC XY: 44AN XY: 74404
ClinVar
Submissions by phenotype
not provided Uncertain:2
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not specified Uncertain:1
DNA sequence analysis of the PMS1 gene demonstrated a sequence change, c.224C>T, in exon 3 that results in an amino acid change, p.Thr75Ile. This sequence change has been described in the gnomAD database with a frequency of 0.1% in the European sub-population (dbSNP rs61756360). The p.Thr75Ile change has been described in the homozygous state in individuals with colorectal cancer (PMID: 26553438). The p.Thr75Ile change affects a highly conserved amino acid residue located in a domain of the PMS1 protein that is known to be functional. The p.Thr75Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Thr75Ile change remains unknown at this time. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at