rs41295288

Variant names:

• chr2-47475052-A-G
• rs41295288
• NM_000251.3:c.1787A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-47475052-A-G
• chr2-47475052-A-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM1 BP4_Moderate BP6 BS1

The NM_000251.3(MSH2):​c.1787A>G​(p.Asn596Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000334 in 1,613,994 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. N596H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:17
• Conservation: PhyloP100: 5.57
• Publications: 27 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 -5 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 36 uncertain in NM_000251.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.12485945).
• BP6: Variant 2-47475052-A-G is Benign according to our data. Variant chr2-47475052-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41646.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000345 (505/1461708) while in subpopulation MID AF = 0.00902 (52/5768). AF 95% confidence interval is 0.00706. There are 1 homozygotes in GnomAdExome4. There are 262 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1787A>G	p.Asn596Ser	missense_variant	Exon 12 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1787A>G	p.Asn596Ser	missense_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000318 AC: 80 AN: 251464 AF XY: 0.000368

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000345 AC: 505 AN: 1461708 Hom.: 1 Cov.: 32 AF XY: 0.000360 AC XY: 262 AN XY: 727174

African (AFR) AF: 0.000448 AC: 15 AN: 33476

American (AMR) AF: 0.000604 AC: 27 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00902 AC: 52 AN: 5768

European-Non Finnish (NFE) AF: 0.000319 AC: 355 AN: 1111862

Other (OTH) AF: 0.000530 AC: 32 AN: 60386

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74464

African (AFR) AF: 0.000313 AC: 13 AN: 41552

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000255 AC: 31

EpiCase AF: 0.000600

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:17

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:6

-

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

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2: BP4, BS3:Supporting, BS1 -

Oct 27, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

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.Asn596Ser variant was identified in 6 of 6092 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer, breast cancer, and ovarian cancer and was not identified in 2712 control chromosomes from healthy individuals (Barnetson 2008, Genuardi 1999, Jalkh 2017, Pal 2012, Viel 1997, Woods 2005). The variant was also identified in the following databases: dbSNP (ID: rs41295288) as "With Uncertain significance allele", ClinVar (3x uncertain significance, including review by expert panel InSiGHT, 1x likely benign, 2x benign), Clinvitae, UMD-LSDB (2x, unclassified variant), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (12x, uncertain significance). The variant was not identified in COGR, Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 82 of 277212 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 7 of 24034 chromosomes (freq: 0.0003), Other in 7 of 6464 chromosomes (freq: 0.001), Latino in 18 of 34416 chromosomes (freq: 0.0005), European in 43 of 126708 chromosomes (freq: 0.0003), Ashkenazi Jewish in 3 of 10152 chromosomes (freq: 0.0003), and South Asian in 4 of 30780 chromosomes (freq: 0.0001). The variant was not observed in the East Asian or Finnish populations. Two studies have identified this variant in a proband from a family with affected family members (father and two paternal first cousins who carried this variant), but it was not present in another paternal first cousin who was diagnosed with CRC and endometrial cancer at 46 and 48 respectively (Genuardi 1999, Viel 1997). The p.Asn596 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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. 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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:3

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Nov 18, 2014

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. -

Sep 27, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000251.3(MSH2):c.1787A>G (p.Asn596Ser) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asn596Ser variant is observed in 19/34,586 (0.0549%) alleles from individuals of gnomAD Latino background in gnomAD, which is greater than expected for the disorder. There is a small physicochemical difference between asparagine and serine, which is not likely to impact secondary protein structure as these residues share similar properties. The serine residue at codon 596 of MSH2 is only present in a single other mammalian species: Lesser Egyptian jerboa. The nucleotide c.1787 in MSH2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not specified Benign:4

Oct 01, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2018

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. -

Jan 06, 2025

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.1787A>G (p.Asn596Ser) results in a conservative amino acid change located in the core domain (IPR007696) 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 0.00025 in 332158 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.00055 within the Latino subpopulation in the gnomAD database v2.1 dataset. This frequency is somewhat lower than the estimated maximum for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (0.00057). However, the variant was reported with a higher allele frequency in the Middle Eastern subpopulation (i.e. 53/6062 alleles; AF: 0.0087), including 1 homozygote, in the gnomAD database v4.1 dataset, suggesting that it is likely a benign polymorphism. The variant, c.1787A>G, has been reported in the literature in individuals affected with tumors belonging to the Lynch syndrome spectrum, and with other tumor phenotypes (e.g. Mangold_2005, Woods_2005, Betz_2010, Maxwell_2015, Raskin_2017, Damaso_2020, Dorling_2021, Fonfria_2021), as well as in controls (e.g. Dorling_2021). A family with this variant suggests lack of segregation with the disease since one of the affected family members did not carry the variant, although four affected family members did carry the variant (Genuardi_1999). One publication indicates the variant co-occurred with a "familial MMR mutation (MSH6)" (Jori_2015), while an additional co-occurrence with a pathogenic variant has been reported via internal testing (MSH2 c.1786_1788delAAT, p.Asn596del), providing supporting evidence for a benign role. Experimental evidence concluded the variant to be neutral (e.g. Damaso_2020, Jia_2021, Scott_2022). The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 18033691, 19669161, 30306255, 34371384, 37262986, 24953332, 35245693, 34127009, 32635641, 35263119, 10978353, 33471991, 34204722, 10573010, 32957588, 26951660, 28202063, 33357406, 22703879, 26517685, 16614121, 31422574, 15849733, 25503501, 36243179, 27600092, 29212164, 31512090, 22949387, 31159747, 8993976, 16203774, 26580448, 36550560). ClinVar contains an entry for this variant (Variation ID: 41646). Based on the evidence outlined above, the variant was classified as benign. -

Lynch syndrome 1 Uncertain:1 Benign:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 09, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Colorectal cancer, non-polyposis Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

May 05, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Benign:1

Dec 02, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.1787A>G (p.Asn596Ser) missense change has a maximum subpopulation frequency of 0.054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/2-47702191-A-G). This variant results in a conservative amino acid change and five of seven in silico tools predict a benign effect of this variant on protein function (BP4). To our knowledge, functional assays have not been performed. The variant has been identified in individuals with colorectal cancer or meeting Bethesda criteria of hereditary non-polyposis colorectal cancer (HPNCC; PMID: 18033691, 29212164, 16203774, 15849733), as well as individuals with unrelated phenotypes and no evidence of HPNCC (PMID: 22703879, 25637381, internal data). A family with this variant suggests lack of segregation since one of the affected family members did not carry the variant (BS4_Supporting; PMID: 10573010). Another report indicates that the variant co-occurred with a familial pathogenic MSH6 variant in one individual (BP2; PMID: 26517685). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS4_Supporting, BP2, BP4. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 03, 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
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.28	N;.;.;.
PhyloP100		5.6
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N;N;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.37	T;T;.;T
Sift4G	Benign	0.34	T;T;.;T
Polyphen		0.012	B;.;.;B
Vest4		0.51
MVP		0.82
MPC		0.0083
ClinPred		0.039	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.26
gMVP		0.37
Mutation Taster		=57/43	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: rs41295288; hg19: chr2-47702191;