2-47475029-T-G

Variant names:

• chr2-47475029-T-G
• rs63750844
• NM_000251.3:c.1764T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.1764T>G​(p.Tyr588*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y588Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: -0.199
• Publications: 11 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47475029-T-G is Pathogenic according to our data. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475029-T-G is described in CliVar as Pathogenic. Clinvar id is 90780.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.1764T>G	p.Tyr588*	stop_gained	Exon 12 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1764T>G	p.Tyr588*	stop_gained	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Lynch-like syndrome Pathogenic:1

Jul 01, 2019

Constitutional Genetics Lab, Leon Berard Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Coding sequence variation introducing premature termination codon -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y588* pathogenic mutation (also known as c.1764T>G), located in coding exon 12 of the MSH2 gene, results from a T to G substitution at nucleotide position 1764. This changes the amino acid from a tyrosine to a stop codon within coding exon 12. This mutation was detected in a patient with ovarian cancer at age 41, urinary bladder cancer at age 53 and six synchronous colon cancers at age 55. One of the colon tumors demonstrated high microsatellite instability and loss of MSH2 protein by immunohistochemistry (Krüger S et al. Hum Mutat, 2003 Apr;21:445-6). In a study of 1721 German probands suspected of HNPCC, this mutation was detected in one family (Mangold E et al. Int J Cancer, 2005 Sep;116:692-702). In addition to the clinical data presented in the literature, This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	0.0062
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.80	D
PhyloP100		-0.20
Vest4		0.97
GERP RS		-4.1
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs63750844; hg19: chr2-47702168;