7-5992012-G-A

Position:

• chr7-5992012-G-A

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.949C>T​(p.Gln317Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,082 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Q317Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: PMS2 NM_000535.7 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 9.56

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]

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 7-5992012-G-A is Pathogenic according to our data. Variant chr7-5992012-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91383.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-5992012-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.949C>T	p.Gln317Ter	stop_gained	9/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.949C>T	p.Gln317Ter	stop_gained	9/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74294

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 19, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jun 26, 2023	The PMS2 c.949C>T (p.Gln317Ter) change is a nonsense variant that is predicted to cause premature protein truncation and loss of normal protein function. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). This variant has been reported as heterozygous in an individual with colon cancer (PMID: 18602922). It has also been observed as homozygous in an individual with constitutional mismatch repair deficiency who presented with medulloblastoma at 8 years of age, adenocarcinoma at 16 years of age, and multiple café-au-lait macules; the adenocarcinoma tumor showed loss of PMS2 on immunohistochemical staining (PMID: 18602922, 19283792). This variant is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as pathogenic. -

Lynch syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

Coding sequence variation resulting in a stop codon -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 2024

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (PMID: 18602922); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 21376568, 20531397, 22577899, 18709565, 18602922, 19283792, 34308104) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 08, 2023

This premature translational stop signal has been observed in individual(s) with colorectal cancer and/or constitutional mismatch repair deficiency (CMMR-D) syndrome (PMID: 18602922, 19283792). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln317*) 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). ClinVar contains an entry for this variant (Variation ID: 91383). 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 20, 2023

The p.Q317* pathogenic mutation (also known as c.949C>T), located in coding exon 9 of the PMS2 gene, results from a C to T substitution at nucleotide position 949. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been previously reported in an individual with colorectal carcinoma diagnosed at age 39 years whose tumor showed loss of PMS2 on immunohistochemical staining (Senter L et al. Gastroenterology. 2008 Aug;135:419-28). It has also been reported in the homozygous state in an individual with constitutional mismatch repair deficiency (CMMRD), whose clinical features included a diagnosis of medulloblastoma at age 8 years, ampullary adenocarcinoma at 16 years, and multiple café au lait macules (Senter L et al. 2008). 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A;A;D
Vest4		0.88
GERP RS		5.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143277125; hg19: chr7-6031643;