7-5973421-A-C

Position:

• chr7-5973421-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong

The NM_000535.7(PMS2):​c.2567T>G​(p.Leu856Arg) 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. L856M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0000067 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4 O:1
• Conservation: PhyloP100: 9.32

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 4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.2567T>G	p.Leu856Arg	missense_variant	15/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.2567T>G	p.Leu856Arg	missense_variant	15/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD3 exomes AF: 0.00000969 AC: 2 AN: 206402 Hom.: 0 AF XY: 0.0000178 AC XY: 2 AN XY: 112490

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: 0.0000221

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000668 AC: 6 AN: 897626 Hom.: 0 Cov.: 12 AF XY: 0.00000650 AC XY: 3 AN XY: 461516

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000794

Gnomad4 OTH exome AF: 0.0000249

GnomAD4 genome Cov.: 12

Alfa AF: 0.0000517 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 01, 2024	The p.L856R variant (also known as c.2567T>G), located in coding exon 15 of the PMS2 gene, results from a T to G substitution at nucleotide position 2567. The leucine at codon 856 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in probands whose Lynch syndrome-associated tumors demonstrated both intact expression and isolated loss of PMS2 expression by immunohistochemistry (Ambry internal data). This variant has also been detected in conjunction with a pathogenic mutation in PMS2 by our laboratory; however, the phase (whether in cis or trans) is not known. The patient's phenotype was suggestive of CMMR-D (Ambry internal data). 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 available evidence, the clinical significance of this variant remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 29, 2023

Not observed at a 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 cancer evaluated with MSI and IHC (Li et al., 2020); This variant is associated with the following publications: (PMID: Fukui2011[Chapter], 31391288) -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

ClinVar contains an entry for this variant (Variation ID: 142260). 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. 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. This missense change has been observed in individuals with colon cancer and/or endometrial cancer (Invitae). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 856 of the PMS2 protein (p.Leu856Arg). 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. -

Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 09-24-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;.;.;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D;.;D;.;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.9	D;D;.;.;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;.;.;.;D
Sift4G	Pathogenic	0.0010	D;D;.;.;.;D
Polyphen		1.0	D;D;.;.;D;D
Vest4		0.77
MutPred		0.61		Gain of disorder (P = 0.0054);.;.;.;.;.;
MVP		0.98
MPC		4.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.96

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: rs587782342; hg19: chr7-6013052;