rs149511545

Variant names:

• chr2-47410208-G-A
• rs149511545
• NM_000251.3:c.481G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47410208-G-A
• chr2-47410208-G-C
• chr2-47410208-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM5 BP4_Moderate BP6

The NM_000251.3(MSH2):​c.481G>A​(p.Val161Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V161A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:5
• Conservation: PhyloP100: 4.17
• Publications: 6 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 1 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 27 uncertain in NM_000251.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47410209-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 565544.
• BP4: Computational evidence support a benign effect (MetaRNN=0.251997).
• BP6: Variant 2-47410208-G-A is Benign according to our data. Variant chr2-47410208-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 182580.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.481G>A	p.Val161Ile	missense_variant	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.481G>A	p.Val161Ile	missense_variant	Exon 3 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152176 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000651

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251476 AF XY: 0.0000368

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727242

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152176 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74342

African (AFR) AF: 0.000651 AC: 27 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15276

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Jan 20, 2023

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; Has not been previously published as pathogenic or benign to our knowledge; A different missense change at this residue (p.Val161Asp) has been reported in the published literature in association with Lynch syndrome (Bianchi et al., 2017); This variant is associated with the following publications: (PMID: 22949387, 11726306, 28905261, 18822302, 21120944, 28785832) -

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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.Val161Ile variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs149511545) as “With Uncertain significance allele”, ClinVar (as uncertain significance by GeneDx, Invitae, and EGL Genetic Diagnostics, and as likely benign by Ambry Genetics). The variant was identified in control databases in 17 of 277208 chromosomes at a frequency of 0.000061 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 15 of 24030 chromosomes (freq: 0.000624), Other in 1 of 6466 chromosomes (freq: 0.000155), Latino in 1 of 34420 chromosomes (freq: 0.000029), while the variant was not observed in the European (Non-Finnish), Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The p.Val161 residue is conserved in in mammals but not in more distantly related organisms and the variant amino acid Isoleucine (Ile) is present in chickens, increasing the likelihood that this variant does not have clinical significance. 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -

Mar 30, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 21, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population, 0.00068 (17/24964 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with renal papillary cell carcinoma (PMID: 29684080 (2018)) and in a large-scale breast cancer association study, the variant was observed in one healthy control individual (PMID: 33471991 (2021)). 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. -

not specified Uncertain:1 Benign:1

Jan 20, 2025

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.481G>A (p.Val161Ile) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) 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 2.8e-05 in 1614058 control chromosomes, predominantly at a frequency of 0.00056 within the African or African-American subpopulation in the gnomAD database (v4). This frequency is at the estimated for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (2.8e-05 vs 0.00057), allowing no conclusion about variant significance. c.481G>A has been reported in the literature in an individual affected with kidney renal papillary cell carcinoma (Yehia_2018). 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 publication have been ascertained in the context of this evaluation (PMID: 29684080). ClinVar contains an entry for this variant (Variation ID: 182580). Based on the evidence outlined above, the variant was classified as likely benign. -

Oct 08, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.481G>A; p.Val161Ile variant (rs149511545), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 182580). However, a different variant at this codon (p.Val161Asp) is reported in families with Lynch syndrome, and functional studies suggest the variant protein has deficient mismatch repair (MMR) activity and stability as well as abnormal subcellular localization (Bianchi 2018, Ollila 2006 and 2008). The p.Val161Ile variant is found in the general population with an overall allele frequency of 0.006% (17/277208 alleles) in the Genome Aggregation Database. The valine at codon 161 is well conserved, but computational analyses (SIFT, PolyPhen-2) predict the p.Val161Ile variant is tolerated. Due to limited information, the clinical significance of the p.Val161Ile variant is uncertain at this time. REFERENCES Bianchi F et al. A germline missense mutation in exon 3 of the MSH2 gene in a Lynch syndrome family: correlation with phenotype and localization assay. Fam Cancer. 2018 Apr;17(2):215-224. Ollila S et al. Mechanisms of pathogenicity in human MSH2 missense mutants. Hum Mutat. 2008 Nov;29(11):1355-63. Ollila S et al. Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein. Gastroenterology. 2006 Nov;131(5):1408-17. -

Lynch syndrome 1 Uncertain:1 Benign:1

Dec 04, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely 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]. -

Oct 20, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.481G>A (p.Val161Ile) missense change has a maximum subpopulation frequency of 0.068% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, however a functional assay using a massively parallel screen in human cells indicated that this variant is functionally neutral (PMID: 33357406). To our knowledge, this variant has not been reported in the literature in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Hereditary cancer-predisposing syndrome 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. -

Oct 01, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MSH2-related disorder Uncertain:1

Jul 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.481G>A variant is predicted to result in the amino acid substitution p.Val161Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.068% of alleles in individuals of African descent in gnomAD, and has been interpreted as both uncertain and likely benign in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/182580). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 29, 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	0.083
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;.;.;.
Eigen	Benign	-0.014
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Uncertain	-0.091	T
MutationAssessor	Benign	1.3	L;.;.;.;.
PhyloP100		4.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.58	N;N;N;.;N
REVEL	Uncertain	0.48
Sift	Benign	0.20	T;T;T;.;T
Sift4G	Benign	0.27	T;T;T;.;T
Polyphen		0.10	B;.;.;.;B
Vest4		0.40
MVP		0.89
MPC		0.0096
ClinPred		0.045	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.43
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149511545; hg19: chr2-47637347;