7-6005919-T-C

Position:

• chr7-6005919-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000535.7(PMS2):​c.136A>G​(p.Ser46Gly) 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. 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. S46I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_000535.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-6005918-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9245.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.136A>G	p.Ser46Gly	missense_variant	2/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.136A>G	p.Ser46Gly	missense_variant	2/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 16, 2017

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. Different missense substitutions at this codon (p.Ser46Ile and p.Ser46Asn) have been determined to be pathogenic (PMID: 22577899, 23709753, 18602922, 24027009). This suggests that the serine residue is critical for PMS2 protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PMS2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with glycine at codon 46 of the PMS2 protein (p.Ser46Gly). The serine residue is highly conserved and there is a small physicochemical difference between serine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.3	M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.89		Loss of disorder (P = 0.1584);Loss of disorder (P = 0.1584);
MVP		0.97
MPC		0.26
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.71

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: rs1554306350; hg19: chr7-6045550;