rs758225108

chr7-5978659-C-Achr7-5978659-C-Gchr7-5978659-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000535.7(PMS2):c.2212G>T(p.Val738Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000798 in 150,384 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V738A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000080 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: -0.826

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03913027).
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2212G>T	p.Val738Phe	missense_variant	13/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2212G>T	p.Val738Phe	missense_variant	13/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes AF: 0.0000798 AC: 12 AN: 150286 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000661

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00231

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000334 AC: 83 AN: 248174 Hom.: 3 AF XY: 0.000476 AC XY: 64 AN XY: 134314

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00267

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000895

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000185 AC: 269 AN: 1451834 Hom.: 12 Cov.: 31 AF XY: 0.000288 AC XY: 208 AN XY: 722272

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00306

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.0000798 AC: 12 AN: 150384 Hom.: 2 Cov.: 32 AF XY: 0.0000818 AC XY: 6 AN XY: 73392

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000660

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00231

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000430 AC: 52

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 4 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant in c.2212G>T (p.Val738Phe) in PMS2 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Val738Phe variant is reported with the allele frequency of 0.03344% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as conflicting - uncertain significance/ likely benign. The amino acid Val at position 738 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIFT and the residue is variable across species. For these reasons, this variant has been classified as Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 03, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jul 07, 2017	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 15, 2022	This missense variant replaces valine with phenylalanine at codon 738 of the PMS2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant was reported in one individual affected with breast cancer and one unaffected individual (PMID: 33471991). This variant has been identified in 83/248174 chromosomes in the general population by the Genome Aggregation Database (gnomAD). However, this observed allele frequency is not considered reliable since the gnomAD dataset does not disambiguate possible interference from homologous sequence in the PMS2CL pseudogene. 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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jul 26, 2021	- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2021

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 738 of the PMS2 protein (p.Val738Phe). The frequency data for this variant in the population databases (gnomAD) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. 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: 548763). 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. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 25, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	1.7
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.;.;.;.
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.93	D;D;.;D;.;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.039	T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.4	D;D;.;.;.;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0050	D;D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;.;.;.;D
Polyphen		0.27	B;P;.;.;P;P
Vest4		0.70
MutPred		0.65		Gain of helix (P = 0.1736);.;.;.;.;.;
MVP		0.58
MPC		3.2
ClinPred		0.24	T
GERP RS		-7.4
Varity_R		0.62
gMVP		0.80

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: rs758225108; hg19: chr7-6018290; COSMIC: COSV56224579; COSMIC: COSV56224579;