NM_000251.3:c.1737A>G

Variant names:

• chr2-47471040-A-G
• rs61756467
• NM_000251.3:c.1737A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000251.3(MSH2):​c.1737A>G​(p.Lys579Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,550,890 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:29
• Conservation: PhyloP100: 1.47

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-47471040-A-G is Benign according to our data. Variant chr2-47471040-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 36570.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47471040-A-G is described in Lovd as [Likely_benign]. Variant chr2-47471040-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00148 (2071/1398534) while in subpopulation MID AF= 0.0102 (56/5504). AF 95% confidence interval is 0.00805. There are 6 homozygotes in gnomad4_exome. There are 1103 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1737A>G	p.Lys579Lys	synonymous_variant	Exon 11 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1737A>G	p.Lys579Lys	synonymous_variant	Exon 11 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00215 AC: 540 AN: 250870 Hom.: 2 AF XY: 0.00230 AC XY: 312 AN XY: 135686

Gnomad AFR exome AF: 0.000744

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00924

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00148 AC: 2071 AN: 1398534 Hom.: 6 Cov.: 24 AF XY: 0.00158 AC XY: 1103 AN XY: 699520

Gnomad4 AFR exome AF: 0.000776

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00884

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00273

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00261

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74514

Gnomad4 AFR AF: 0.000697

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00192 Hom.: 0

Bravo AF: 0.00149

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00308

ClinVar

Significance: Likely benign

Submissions summary: Benign:29

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:6

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 12, 2013

GeneDx

Significance: 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. -

Oct 03, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:6

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2017

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2019

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 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. -

Aug 07, 2015

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:6

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2: BP4, BP7 -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5

Jan 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 02, 2021

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Apr 30, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 08, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:2

Feb 17, 2015

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: research

Synonymous substitution with no effect on splicing, tested with an NMD inhibitor. Multifactorial likelihood analysis posterior probability 0.001-0.049 -

Breast and/or ovarian cancer Benign:1

Jul 09, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH2-related disorder Benign:1

Jan 10, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Carcinoma of colon Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Lys579Lys variant has been identified in 5 out of 3696 proband chromosomes (frequency 0.001) in colorectal patients with Bethesda, Amsterdam or HNPCC criteria, and in 1 out of 400 control chromosomes (frequency 0.003) (Curia 1999, Scartozzi 2002, Auclair 2005, Mangold 2005, Pastrello 2011). it is listed in dbSNP database (‘with unknown allele’) (ID#: rs61756467) with an average heterozygosity of 0.002+/-0.030, therefore increasing the likelihood that this variant is benign. In addition, this variant is not expected to have clinical significance because it does not alter an amino acid residue, and is not located near a splice junction. In summary, based on the above information this variant is classified as Benign. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	6.0
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs61756467; hg19: chr2-47698179;