NM_000251.3:c.2551C>G

Variant names:

• chr2-47480788-C-G
• rs267608015
• NM_000251.3:c.2551C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000251.3(MSH2):​c.2551C>G​(p.Leu851Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L851I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 1.90
• Publications: 7 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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2551C>G	p.Leu851Val	missense_variant	Exon 15 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2551C>G	p.Leu851Val	missense_variant	Exon 15 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727204

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: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:3

Aug 09, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 851 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer who had two or more family members affected with Lynch syndrome-associated cancers (PMID 18726168), as well as in an individual affected with ovarian, peritoneal, or fallopian tube carcinoma (PMID: 22006311). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L851V variant (also known as c.2551C>G), located in coding exon 15 of the MSH2 gene, results from a C to G substitution at nucleotide position 2551. The leucine at codon 851 is replaced by valine, an amino acid with highly similar properties. This alteration was seen in 1/85 Asian patients with personal history of cancer and meeting Amsterdam I/II criteria (Yap HL et al. Fam Cancer, 2009 Aug;8:85-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Sep 25, 2024

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting, PP3, BS3 c.2551C>G, located in exon 15 of the MSH2 gene, is predicted to result in the substitution of Leu by Val at codon 851, p.(Leu851Val). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). Computational tools for this variant suggests no significant impact on splicing but predict a deleterious effect of the variant on protein function (MAPP+PolyPhen-2 prior probability for pathogenicity: 0.91) (PP3). A functional study based on cell viability assay in HEK293 or HAP1 cells using 6-TG treatment demonstrates normal function for this variant, with a LOF score -4,66 (PMID 33357406) (BS3). There are no reports of pathogenic missense variants in the same codon. This variant has been identified together with a pathogenic mutation in MLH1 gene, in a patient affected with endometrial, colorectal and breast cancer (no tumour information available; internal data). Based on currently available information, the variant c.2551C>G should be considered an uncertain significance variant. -

Lynch syndrome 1 Uncertain:2

Nov 05, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2024

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 15 of the MSH2 gene that results in the amino acid substitution of Valine for Leucine at codon 851 was detected. The observed variation is documented as variant of uncertain significance in Lynch syndrome in the ClinVar database [VCV000141396.23]. It lies in the MutS domain V domain of the MSH2_HUMAN protein (PF00488). The p.Leu851Val variant has not been reported in the 1000 genomes and gnomAD databases. The in-silico predictions of the variant are probably damaging by PolyPhen-2 (Hum_Div) and damaging by SIFT, LRT, Mutation Taster2 tools. The reference codon is conserved across species. -

Lynch syndrome Uncertain:1

Aug 23, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 851 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in an individual affected with colorectal cancer who had two or more family members affected with Lynch syndrome-associated cancers (PMID 18726168), as well as in an individual affected with ovarian, peritoneal, or fallopian tube carcinoma (PMID: 22006311). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Apr 28, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22006311, 27930734) -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 851 of the MSH2 protein (p.Leu851Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with MSH2-associated cancer (PMID: 22006311). ClinVar contains an entry for this variant (Variation ID: 141396). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
PhyloP100		1.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D;D;.;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.80
MutPred		0.80		Loss of catalytic residue at L851 (P = 0.0969);.;Loss of catalytic residue at L851 (P = 0.0969);Loss of catalytic residue at L851 (P = 0.0969);
MVP		0.90
MPC		0.032
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.86
gMVP		0.60
Mutation Taster		=56/44	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: rs267608015; hg19: chr2-47707927;