2-47471062-G-T

Position:

• chr2-47471062-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000251.3(MSH2):​c.1759G>T​(p.Gly587Cys) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G587R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a helix (size 2) in uniprot entity MSH2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47471062-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 90771.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47471062-G-T is Pathogenic according to our data. Variant chr2-47471062-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 428463.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-47471062-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.1759G>T	p.Gly587Cys	missense_variant, splice_region_variant	11/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.1759G>T	p.Gly587Cys	missense_variant, splice_region_variant	11/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2024

The c.1759G>T pathogenic mutation (also known as p.G587C), located in coding exon 11 of the MSH2 gene, results from a G to T substitution at nucleotide position 1759. The amino acid change results in glycine to cysteine at codon 587, an amino acid with highly dissimilar properties. However, this change occurs in the last base pair of coding exon 11, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated loss of MSH2 expression by immunohistochemistry (Ambry internal data).This mutation was reported in a proband with HNPCC, and RNA analysis confirmed it resulted in aberrant splicing yielding p.Ser554Argfs*11 (Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31). In addition, an ex vivo minigene splicing assay on genomic DNA revealed exon 11 skipping as a result of another alteration at this position (c.1759G>C; p.G587R), which as been detected in one suspected Lynch syndrome family and has been classified as pathogenic by multifactorial analysis (Bonadona V et al. JAMA, 2011 Jun;305:2304-10; Tournier I et al. Hum. Mutat. 2008 Dec;29:1412-24; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-115). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.4	D;D;.;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.0050	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.83
MutPred		0.49		Loss of glycosylation at S586 (P = 0.0485);.;Loss of glycosylation at S586 (P = 0.0485);Loss of glycosylation at S586 (P = 0.0485);
MVP		0.97
MPC		0.035
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63751140; hg19: chr2-47698201;