chr7-6009013-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000535.7(PMS2):c.7C>T(p.Arg3Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R3R) has been classified as Likely benign.
Frequency
Consequence
NM_000535.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PMS2 | NM_000535.7 | c.7C>T | p.Arg3Ter | stop_gained | 1/15 | ENST00000265849.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PMS2 | ENST00000265849.12 | c.7C>T | p.Arg3Ter | stop_gained | 1/15 | 1 | NM_000535.7 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460206Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726424
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 15, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2017 | This variant is denoted PMS2 c.7C>T at the cDNA level and p.Arg3Ter (R3X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. - |
Lynch syndrome 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 15, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 25, 2023 | This sequence change creates a premature translational stop signal (p.Arg3*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PMS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 234658). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2021 | The p.R3* pathogenic mutation (also known as c.7C>T), located in coding exon 1 of the PMS2 gene, results from a C to T substitution at nucleotide position 7. This changes the amino acid from an arginine to a stop codon within coding exon 1. This alteration was reported in a cohort of women undergoing multigene panel testing for hereditary cancer risk (Roberts ME et al. Genet Med, 2018 10;20:1167-1174). In another report, this alteration was identified in a proband with colorectal cancer diagnosed at age 44 that demonstrated high microsatellite instability (MSI-H) and loss of MLH1 protein expression by immunohistochemistry (IHC); however, PMS2 protein expression was reported to be non-interpretable (Wang Q et al. J Med Genet, 2020 07;57:487-499). This alteration was also identified in conjunction with a somatic pathogenic PMS2 variant in a proband whose MSI-H Lynch syndrome-associated tumor demonstrated isolated loss of PMS2 protein expression on IHC (Ambry internal data). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at