2-47476367-G-T

Variant names:

• chr2-47476367-G-T
• rs63751640
• NM_000251.3:c.2006G>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000251.3(MSH2):​c.2006G>T​(p.Gly669Val) 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. 15/24 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G669C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 7.68
• Publications: 15 publications found

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]

MSH2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 20 benign, 24 uncertain 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 chr2-47475270-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 486870.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-47476367-G-T is Pathogenic according to our data. Variant chr2-47476367-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 90854.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2006G>T	p.Gly669Val	missense_variant, splice_region_variant	Exon 13 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2006G>T	p.Gly669Val	missense_variant, splice_region_variant	Exon 13 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000482 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Aug 17, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported to segregate with disease in families with Lynch syndrome (PMID: 27629256 (2017), and the UMD database (http://www.umd.be/)). In addition, experimental studies indicate that the variant causes an out-of-frame skipping of exon 13 in the MSH2 mRNA, and has deleterious effects on DNA mismatch repair activity in vitro (PMIDs: 27629256 (2017) and 26247049 (2015)). Based on the available information, this variant is classified as pathogenic. -

Dec 13, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Alters the first nucleotide of the exon and is demonstrated to lead to loss of exon 13 which leads to a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 26247049); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24362816, 28422960, 18822302, 21120944, 27629256, 26247049, 36612224) -

Lynch syndrome 1 Pathogenic:1

Aug 07, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 26247049, 27629256]. Functional studies indicate this variant impacts protein function [PMID: 27629256]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Variant causes splicing aberration (full inactivation of variant allele) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 669 of the MSH2 protein (p.Gly669Val). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 10612827, 21520333, 27629256; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90854). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 27629256, 28422960). Studies have shown that this missense change results in partial or complete exclusion of exon 13 and introduces a premature termination codon (PMID: 26247049, 27629256). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 10, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G669V pathogenic mutation (also known as c.2006G>T) is located in coding exon 13 of the MSH2 gene. The glycine at codon 669 is replaced by valine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 13 and has been confirmed to cause skipping of exon 13 (van der Klift HM et al. Mol Genet Genomic Med. 2015 Jul;3:327-45; Tricarico R et al. Hum Mutat. 2017 01;38:64-77). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome (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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified Uncertain:1

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	5.0	H;.;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.7	D;D;.;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.98
MVP		0.98
MPC		0.032
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
Splicevardb		3.0
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs63751640; hg19: chr2-47703506;