rs763866879

Variant names:

• chr7-5982897-G-A
• rs763866879
• NM_000535.7:c.2101C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000535.7(PMS2):​c.2101C>T​(p.His701Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 7-5982897-G-A is Pathogenic according to our data. Variant chr7-5982897-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411077.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.2101C>T	p.His701Tyr	missense_variant	Exon 12 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.2101C>T	p.His701Tyr	missense_variant	Exon 12 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000451 AC: 1 AN: 221718 Hom.: 0 AF XY: 0.00000829 AC XY: 1 AN XY: 120666

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: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 17, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H701Y variant (also known as c.2101C>T), located in coding exon 12 of the PMS2 gene, results from a C to T substitution at nucleotide position 2101. The histidine at codon 701 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in a proband with MSI-H colorectal cancer and has also been identified as somatic in conjunction with copy neutral loss of heterozygosity (CN-LOH) in a MSI-H endometrial tumor with isolated loss of PMS2 protein expression by immunohistochemistry (IHC) (Ambry internal data). Based on internal structural analysis, this variant sits at the interface between PMS2/MutLa and is anticipated to result in a significant decrease in structural stability (Gueneau E et al. Nat Struct Mol Biol, 2013 Apr;20:461-8; Ambry internal data). Another alteration at the same codon, p.H701R (c.2102A>G), was also determined to be structurally destabilizing and was detected in a proband whose MSI-H colon cancer demonstrated isolated loss of PMS2 protein expression by IHC (Ambry internal data). Furthermore, the proband had a strong family history of HNPCC/Lynch syndrome-related cancers (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 701 of the PMS2 protein (p.His701Tyr). 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: 411077). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt PMS2 function with a positive predictive value of 95%. 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. -

Lynch syndrome 4 Uncertain:1

Mar 22, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;.;D;.;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.7	H;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.0	D;D;.;.;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;.;.;D
Sift4G	Uncertain	0.0020	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.95
MutPred		0.87		Loss of catalytic residue at H701 (P = 0.0524);.;.;.;.;.;
MVP		0.96
MPC		3.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.88

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: rs763866879; hg19: chr7-6022528;