7-5977703-G-C

Position:

• chr7-5977703-G-C

Variant summary

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

The NM_000535.7(PMS2):​c.2330C>G​(p.Thr777Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.18

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2330C>G	p.Thr777Ser	missense_variant	14/15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2330C>G	p.Thr777Ser	missense_variant	14/15	1	NM_000535.7	ENSP00000265849	P3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250194 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455898 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724264

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2023	The p.T777S variant (also known as c.2330C>G), located in coding exon 14 of the PMS2 gene, results from a C to G substitution at nucleotide position 2330. The threonine at codon 777 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2022	This missense variant replaces threonine with serine at codon 777 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. This variant has not been reported in individuals affected with PMS2-related disorders in the literature. This variant has been identified in 1/250194 chromosomes 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 777 of the PMS2 protein (p.Thr777Ser). 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: 411065). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.;.;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D;.;D;.;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	D;D;.;.;.;D
REVEL	Uncertain	0.43
Sift	Benign	0.067	T;T;.;.;.;T
Sift4G	Benign	0.47	T;T;.;.;.;T
Polyphen		0.38	B;D;.;.;D;D
Vest4		0.70
MutPred		0.42		Gain of loop (P = 0.069);.;.;.;.;.;
MVP		0.88
MPC		3.0
ClinPred		0.87	D
GERP RS		5.8
Varity_R		0.32
gMVP		0.41

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: rs777728316; hg19: chr7-6017334;