chr2-47475029-T-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000251.3(MSH2):​c.1764T>C​(p.Tyr588Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 2-47475029-T-C is Benign according to our data. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47475029-T-C is described in CliVar as Benign/Likely_benign. Clinvar id is 187608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.199 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1764T>C	p.Tyr588Tyr	synonymous_variant	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>C	p.Tyr588Tyr	synonymous_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251374 AF XY: 0.0000442

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461278 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111488

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Dec 23, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 22, 2019

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1

Dec 11, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Lynch syndrome Benign:1

May 16, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2: BP4, BP7 -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.47
DANN	Benign	0.38
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs63750844; hg19: chr2-47702168;