chr7-5997348-CG-C

Position:

• chr7-5997348-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000535.7(PMS2):​c.780delC​(p.Asp261fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S260S) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 27)
• Consequence: PMS2 NM_000535.7 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: -2.26

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-5997348-CG-C is Pathogenic according to our data. Variant chr7-5997348-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 91367.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5997348-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.780delC	p.Asp261fs	frameshift_variant	7/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.780delC	p.Asp261fs	frameshift_variant	7/15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 27

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 07, 2017	The p.Asp261fs variant in PMS2 has been identified as a germline variant in 1 in dividual with Lynch syndrome (with PMS2-negative colorectal cancer; Borras 2013) and was absent from large population studies. This variant is predicted to caus e a frameshift, which alters the protein?s amino acid sequence beginning at posi tion 261 and leads to a premature termination codon 46 amino acids downstream. T his alteration is then predicted to lead to a truncated or absent protein. Heter ozygous loss of function of the PMS2 gene is an established disease mechanism fo r Lynch syndrome. Additionally, this variant was classified as Pathogenic on Sep tember 5, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV00010838 2.2). In summary, the p.Asp261fs variant meets criteria to be classified as path ogenic for Lynch syndrome in an autosomal dominant manner. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 08, 2023	The c.780del (p.Asp261Metfs*46) variant in the PMS2 gene is located on the exon 7 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asp261Metfs*46), resulting in an absent or disrupted protein product. The variant has been reported in an individual with colorectal cancer and immunohistochemical analysis showed loss of PMS2 expression (PMID: 23709753). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 28514183, 25512458, 35223509). The variant is reported in ClinVar as pathogenic (ID: 91367) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.780del (p.Asp261Metfs*46) variant of PMS2 has been classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	Coding sequence variation resulting in a stop codon -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 16, 2023

This sequence change creates a premature translational stop signal (p.Asp261Metfs*46) 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 premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 23709753). ClinVar contains an entry for this variant (Variation ID: 91367). 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

Sep 07, 2021

The c.780delC pathogenic mutation, located in coding exon 7 of the PMS2 gene, results from a deletion of one nucleotide at nucleotide position 780, causing a translational frameshift with a predicted alternate stop codon (p.D261Mfs*46). This alteration has been identified in a female diagnosed with MSI-high colorectal cancer at age 48; this tumor showed loss of PMS2 on immunohistochemistry (Borràs E et al. J. Med. Genet., 2013 Aug;50:552-63). 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: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587779344; hg19: chr7-6036979;