2-47429886-C-G

Variant names:

• chr2-47429886-C-G
• rs63750813
• NM_000251.3:c.1221C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_000251.3(MSH2):​c.1221C>G​(p.Leu407Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,024 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L407L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0680
• Publications: 6 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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.063).
• BP6: Variant 2-47429886-C-G is Benign according to our data. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47429886-C-G is described in CliVar as Benign/Likely_benign. Clinvar id is 90570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.068 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1221C>G	p.Leu407Leu	synonymous_variant	Exon 7 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1221C>G	p.Leu407Leu	synonymous_variant	Exon 7 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251412 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41528

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Oct 12, 2022

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. -

Jan 15, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The synonymous variant NM_000251.3(MSH2):c.1221C>G (p.Leu407=) has been reported to ClinVar as Likely benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 90570 as of 2025-01-02). The p.Leu407= variant is not predicted to disrupt an existing splice site. The p.Leu407= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Likely Benign. -

Oct 27, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Feb 15, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 30, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:2

Dec 06, 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. -

Jun 27, 2024

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 Benign:1

Apr 21, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

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	-0.50
CADD	Benign	5.0
DANN	Benign	0.75
PhyloP100		-0.068
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: rs63750813; hg19: chr2-47657025;