rs41295296

Variant names:

• chr2-47480740-A-C
• rs41295296
• NM_000251.3:c.2503A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47480740-A-C
• chr2-47480740-A-G
• chr2-47480740-A-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000251.3(MSH2):​c.2503A>C​(p.Asn835His) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N835I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:5
• Conservation: PhyloP100: 4.40
• Publications: 14 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24905026).
• BP6: Variant 2-47480740-A-C is Benign according to our data. Variant chr2-47480740-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 90988.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2503A>C	p.Asn835His	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.2503A>C	p.Asn835His	missense_variant	Exon 15 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251448 AF XY: 0.0000221

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: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.000100 AC XY: 73 AN XY: 727206

African (AFR) AF: 0.0000299 AC: 1 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: 39676

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

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000134 AC: 149 AN: 1111976

Other (OTH) AF: 0.0000331 AC: 2 AN: 60390

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74356

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3 Benign:1

Oct 22, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2503A>C, in exon 15 that results in an amino acid change, p.Asn835His. This sequence change has been described in the gnomAD database with a low population frequency of 0.008% in the non-Finnish European subpopulation (dbSNP rs41295296). It has been previously described in patients with colorectal cancer, ovarian cancer, breast cancer and endometrial cancer (PMIDs: 19117025, 25503501, 16885385, 18033691). This variant was classified as benign based on its presence in one healthy control and lack of microsatellite instability in the colon tumor of one patient (PMID: 18033691). The p.Asn835His change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Asn835His substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn835His change remains unknown at this time. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Classification criteria: BS1, BS3 -

Dec 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn835His variant in MSH2 has been reported in 2 individuals with Lynch sy ndrome-associated cancers (Hampel 2006, Barnetson 2008), where a lack of microsa tellite instability was observed in one of the individuals' colon tumor. This va riant has also been identified in 1/66684 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41295296). Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. Furthermore, this variant was cl assified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen- approved InSiGHT expert panel (ClinVar SCV000107519.2). In summary, the clinical significance of the p.Asn835His variant is uncertain. -

Oct 13, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.2503A>C (p.Asn835His) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2503A>C has been reported in the literature among individuals affected with endometrial cancer with uncertain MSI status (Hampel_2006), a colorectal cancer patient with MSI-low tumor, Tumor IHC positive for MLH1, MSH2, MSH6 (Barneston_2008), breast/ovarian cancer with negative BRCA testing (Maxwell_2014, South_2009, Jarhelle_2019, Bhai_2021, Li_2020), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 34326862, 16885385, 26951660, 31882575, 31391288, 25503501, 19117025). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=8, benign/likely benign, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Lynch syndrome 1 Uncertain:2 Benign:1

Dec 13, 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

Apr 27, 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. -

Dec 06, 2015

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Jul 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. -

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:2

Nov 20, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.2503A>C (p.Asn835His) variant has been reported in the published literature in individuals with Lynch syndrome (PMID: 21671081 (2011)) and Lynch-related cancers such as endometrial cancer (PMID: 16885385 (2006)) and colorectal cancer (PMID: 18033691 (2008)). Additionally, this variant has been reported in individuals with ovarian cancer (PMID: 19117025 (2009)), breast cancer (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/), 31882575 (2019), 25503501 (2015)), and reportedly healthy individuals (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/)). Experimental studies suggest this variant has a neutral impact on protein function (PMID: 33357406 (2021), 26951660 (2016)). The frequency of this variant in the general population, 0.000077 (10/129166 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 17, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22949387, 31391288, 18033691, 16885385, 19117025, 26333163, 22290698, 25503501, 21671081, 17531815, 21153778, 30798936, 31882575) -

MSH2-related disorder Uncertain:1

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.2503A>C variant is predicted to result in the amino acid substitution p.Asn835His. This variant has been reported in individuals with colorectal, ovarian, breast, and endometrial cancer (Table S1, Hampel et al. 2006. PubMed ID: 16885385; Table 1, Barnetson et al. 2008. PubMed ID: 18033691; Table 3, South et al. 2009. PubMed ID: 19117025; Table S1, Maxwell et al. 2015. PubMed ID: 25503501; Table S4, Bhai et al. 2021. PubMed ID: 34326862). It has also been reported in a control individual from a colorectal cancer cohort study (Table 1, Barnetson et al. 2008. PubMed ID: 18033691). It is predicted to be tolerated by in silico tools (George Priya Doss et al. 2010. PubMed ID: 21153778). This variant is reported in 0.0077% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90988/). 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

Feb 05, 2024

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 asparagine with histidine at codon 835 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 several individuals affected with Lynch syndrome-associated cancers including colorectal (PMID: 18033691, 21671081), ovarian (PMID: 19117025), and endometrial cancer (PMID: 16885385). One individual with colorectal cancer showed high microsatellite instability and loss of MSH2 protein via immunohistochemistry (IHC) analysis, however, this individual also carried another MSH2 variant (PMID: 21671081). Another individual affected with colorectal cancer demonstrated low microsatellite instability and presence of MSH2 protein by IHC analysis (PMID: 18033691). The individual affected with endometrial cancer demonstrated intact MSH2 protein by IHC analysis, but did show loss of MLH1 protein and MLH1 methylation (PMID: 16885385). This variant has also been observed in two individuals affected with early onset breast cancer (PMID: 25503501, 31882575), an individual affected with breast and uterine cancer (PMID: 34326862), and in a large breast cancer case-control study it was observed in 17 affected and 7 unaffected individuals (PMID: 33471991). This variant has been identified in 10/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available evidence indicates that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Feb 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 27, 2024

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	0.068
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.18	N;.;.;.
PhyloP100		4.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.43	N;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.30	T;T;.;T
Sift4G	Benign	0.34	T;T;.;T
Polyphen		0.0010	B;.;.;B
Vest4		0.43
MVP		0.83
MPC		0.0064
ClinPred		0.13	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.20
Mutation Taster		=76/24	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: rs41295296; hg19: chr2-47707879;