rs786202567

chr7-5992027-T-Achr7-5992027-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000535.7(PMS2):c.934A>T(p.Met312Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M312I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.321

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13920695).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.934A>T	p.Met312Leu	missense_variant	9/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.934A>T	p.Met312Leu	missense_variant	9/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 27, 2024	The p.M312L variant (also known as c.934A>T), located in coding exon 9 of the PMS2 gene, results from an A to T substitution at nucleotide position 934. The methionine at codon 312 is replaced by leucine, an amino acid with highly similar properties. This variant was detected in 1/1197 individuals with a personal or family history of breast and/or ovarian cancer from a Greek, Romanian, and Turkish cohort (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

May 16, 2023

This missense variant replaces methionine with leucine at codon 312 of the PMS2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 312 of the PMS2 protein (p.Met312Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 584547). 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 not expected to disrupt PMS2 protein function with a negative predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	14
Dann	Benign	0.45
DEOGEN2	Benign	0.19	T;.;.;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.69
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.79	T;T;.;T;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.50	N;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;N;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	0.42	T;T;.;.;.
Sift4G	Benign	0.29	T;T;.;.;.
Polyphen		0.0010	B;B;.;.;B
Vest4		0.29
MutPred		0.56		Loss of helix (P = 0.1299);.;.;.;.;
MVP		0.70
MPC		0.035
ClinPred		0.058	T
GERP RS		1.2
Varity_R		0.31
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs786202567; hg19: chr7-6031658;