2-47463105-C-G

Variant names:

• chr2-47463105-C-G
• rs35107951
• NM_000251.3:c.1461C>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000251.3(MSH2):​c.1461C>G​(p.Asp487Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,613,820 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:6
• Conservation: PhyloP100: -0.0690

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038699567).
• BP6: Variant 2-47463105-C-G is Benign according to our data. Variant chr2-47463105-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90674.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1461C>G	p.Asp487Glu	missense_variant	Exon 9 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1461C>G	p.Asp487Glu	missense_variant	Exon 9 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251314 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135832

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1461692 Hom.: 1 Cov.: 31 AF XY: 0.000151 AC XY: 110 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74320

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Jan 02, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS3_moderate -

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 p.Asp487Glu variant was identified in 4 of 9048 proband chromosomes (frequency: 0.0004) from individuals or families with endometrial, ovarian, or breast cancer and was not identified in 280 control chromosomes from healthy individuals (Hampel 2006, Pal 2012, Chubb 2015, Shirts 2015). The variant was also identified in the following databases: dbSNP (ID: rs35107951), ClinVar and Clinvitae (classified 5x as uncertain significance by InSiGHT, GeneDx, Invitae, University of Washington, Counsyl; classified 1x as likely benign by Ambry Genetics), Insight Colon Cancer Gene Variant Database (1x uncertain significance), Insight Hereditary Tumors Database (1x uncertain significance). The variant was not identified in the COGR, COSMIC, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant databases. The variant was identified in control databases in 13 of 277100 chromosomes at a frequency of 0.00005 in the following populations: European non-Finnish 12 of 126606 chromosomes (freq. 0.00009) and African in 1 of 24036 chromosomes (freq. 0.00004) (Genome Aggregation Consortium Feb 27, 2017). An in vitro functional study found this variant’s repair efficiency to be significantly decreased measured at 10% relative to wild type MSH2 (Kantelinen 2012). The p.Asp487Glu residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. An in silico classification tool (PON-MMR2) developed specifically for mismatch repair variants classified this variant as benign (Niroula 2015). The variant is located within the DNA mismatch repair protein MutS core, MutS clamp, and MSH2 functional domains. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jan 10, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22290698, 22581703, 16885385, 15872200, 25559809, 23047549, 23718828, 26845104, 26333163, 21153778, 29641532) -

Lynch syndrome 1 Uncertain:2 Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Mar 18, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

May 25, 2018

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 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2018

True Health Diagnostics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:1

Jul 29, 2022

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.1461C>G, in exon 9 that results in an amino acid change, p.Asp487Glu. This sequence change does not appear to have been previously described in individuals with MSH2-related disorders and has been described in the gnomAD database with a frequency of 0.0046% in the overall population (dbSNP rs35107951). The p.Asp487Glu change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Asp487Glu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asp487Glu change remains unknown at this time. -

Feb 21, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.1461C>G (p.Asp487Glu) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Bioinformatic approaches evaluating functional effects for 168 MMR missense variants have predicted this variant to be neutral (example, Ali_2012).The variant allele was found at a frequency of 4.4e-05 in 251594 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 0.00057), allowing no conclusion about variant significance. c.1461C>G has been reported in the literature among individuals with colorectal cancer who did not fulfill either Amsterdam-II nor Bethesda criteria, had low MSI, normal MSH2 staining on IHC and hypermethylation of MLH1 promoter suggestive of a sporadic etiology of disease (example, Hampel_2005, Hampel_2006). It has also been reported as a VUS in settings of multigene panel testing of cohorts with colorectal/epithelial ovarian cancer (example, Chubb_2015, Pal_2012) These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Kantelinen_2012). The most pronounced variant effect results in approximately 50% of normal in vitro MMR activity. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=7). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer Uncertain:1

May 04, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH2-related disorder Uncertain:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.1461C>G variant is predicted to result in the amino acid substitution p.Asp487Glu. This variant has been reported in multiple cancer types, including: breast, ovarian, endometrial, and multiple individuals with colorectal cancer (Hampel et al. 2005. PubMed ID: 15872200; Hampel et al. 2006. PubMed ID: 16885385; Pal et al. 2012. PubMed ID: 23047549; Chubb et al. 2015. PubMed ID: 25559809; Shirts et al. 2016. PubMed ID: 26845104). Functional studies indicate that this variant results in decreased mismatch repair; however, a common benign polymorphism had similar results (Kantelinen et al. 2012, PubMed ID: 22581703). This variant is reported in 0.0093% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/90674/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Lynch syndrome Uncertain:1

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 30, 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
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	7.9
DANN	Benign	0.63
DEOGEN2	Benign	0.34	T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	-0.94	N;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.020	N;N;.;N
REVEL	Uncertain	0.44
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.0	B;.;.;B
Vest4		0.20
MutPred		0.43		Gain of ubiquitination at K490 (P = 0.1278);.;Gain of ubiquitination at K490 (P = 0.1278);Gain of ubiquitination at K490 (P = 0.1278);
MVP		0.89
MPC		0.0066
ClinPred		0.047	T
GERP RS		0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.19

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: rs35107951; hg19: chr2-47690244;