rs778251286

chr7-5982962-A-Gchr7-5982962-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000535.7(PMS2):c.2036T>C(p.Ile679Thr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic 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. I679V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000085 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 9.24

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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2036T>C	p.Ile679Thr	missense_variant	12/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2036T>C	p.Ile679Thr	missense_variant	12/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000500 AC: 1 AN: 200150 Hom.: 0 AF XY: 0.00000915 AC XY: 1 AN XY: 109246

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000119

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000845 AC: 12 AN: 1419750 Hom.: 0 Cov.: 26 AF XY: 0.00000567 AC XY: 4 AN XY: 705084

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: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000102

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 19, 2017	Variant summary: The PMS2 c.2036T>C (p.Ile679Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 1/44144 control chromosomes at a frequency of 0.0000227, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). It was reported in one patient with suspected LS, however without strong evidence for pathogenicity. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal cancer whose tumor revealed normal mismatch repair immunohistochemistry (Carneiro da Silva et al., 2015); This variant is associated with the following publications: (PMID: 26437257, 28874130) -

Lynch syndrome 4 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 04, 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	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Apr 22, 2021

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 679 of the PMS2 protein (p.Ile679Thr). 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 missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 26437257, 28874130). ClinVar contains an entry for this variant (Variation ID: 229989). 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 expected to disrupt PMS2 protein function with a positive 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2022

The p.I679T variant (also known as c.2036T>C), located in coding exon 12 of the PMS2 gene, results from a T to C substitution at nucleotide position 2036. The isoleucine at codon 679 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a Brazilian patient with colorectal cancer diagnosed at age 50 that had intact immunohistochemistry staining for all four mismatch repair proteins and whose family history met revised Bethesda guidelines (Carneiro da Silva F et al. PLoS ONE, 2015 Oct;10:e0139753). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D;.;D
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Pathogenic	3.2	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.8	D;D;.;.;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.013	D;D;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;.;.;.;D
Polyphen		0.96	D;D;.;.;D;P
Vest4		0.89
MutPred		0.74		Loss of stability (P = 0.0233);.;.;.;.;.;
MVP		0.93
MPC		3.3
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.51
gMVP		0.77

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: rs778251286; hg19: chr7-6022593;