2-47470993-A-G

Variant names:

• chr2-47470993-A-G
• rs55778204
• NM_000251.3:c.1690A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_000251.3(MSH2):​c.1690A>G​(p.Thr564Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000588 in 1,564,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T564N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:16
• Conservation: PhyloP100: 2.41
• 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: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 31 uncertain in NM_000251.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.024828196).
• BP6: Variant 2-47470993-A-G is Benign according to our data. Variant chr2-47470993-A-G is described in ClinVar as Benign. ClinVar VariationId is 90750.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1690A>G	p.Thr564Ala	missense_variant	Exon 11 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1690A>G	p.Thr564Ala	missense_variant	Exon 11 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 250388 AF XY: 0.000199

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000545 AC: 77 AN: 1411704 Hom.: 0 Cov.: 25 AF XY: 0.0000496 AC XY: 35 AN XY: 705514

African (AFR) AF: 0.00 AC: 0 AN: 32520

American (AMR) AF: 0.0000448 AC: 2 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25796

East Asian (EAS) AF: 0.00145 AC: 57 AN: 39360

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5492

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1067066

Other (OTH) AF: 0.000205 AC: 12 AN: 58562

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74490

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Uncertain:1 Benign:2

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

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 10, 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.

not provided Benign:3

Feb 02, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MSH2 c.1690A>G (p.Thr564Ala) variant involves the alteration of a conserved nucleotide. 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index). This variant was found in 22/120830 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.002547 (22/8638). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant was found in several studies assessing colorectal cancer patients with normal IHC and microsatellite stable tumors; however no strong evidence for pathogenicity were present. Furthermore, in one family the variant did not co-segregate with the disease, and the cause of cancer in this family was attributed to a pathogenic variant in the APC gene, further supporting a neutral outcome. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Considering all evidence, the variant is classified as Benign.

Oct 14, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22290698, 15996210, 24362816, 12200596, 18726168, 24735542, 17192056, 25980754, 24710284, 26900293, 29506494)

Jul 30, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:3

Sep 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 23, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Dec 14, 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.

not specified Benign:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 02, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in 0.25% of East Asian chrs (0.31% in gnomAD - too high for disease frequency). It is classified in ClinVar with 3 stars as benign by an expert panel (InSiGHT) and Invitae. It has been reported in 3 papers: in one it did not segregate in the family with disease, in one it was predicted to be not pathogenic, and one where MSH2 expression was retained. Rabbit also has an Alanine at this position.

Breast and/or ovarian cancer Benign:1

Oct 06, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Carcinoma of colon Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 p.Thr564Ala variant was identified in 8 of 468 proband chromosomes (frequency: 0.02) from Chinese and Taiwanese individuals or families with HNPCC/suspected HNPCC related CRC (Chang_2016_26900293, Lee_2005_15996210, Yap_2009_18726168). In a 4 generation Han Chinese family affected with polyposis, sequencing of 5 genes related to HNPCC/FAP found the variant to co-occur with a truncating APC variant (c.694C>), and the variant was found in both affected and unaffected members (Zhang_2014_24735542). Two bioinformatics prediction models pathogenic-or-not mismatch repair (PONMMR), and multivariate analysis of protein polymorphisms–mismatch repair (MAPP-MMR) assessed the variant as neutral (Ali_2012_22290698, Chao_2008_18383312). The variant was also identified in dbSNP (ID: rs55778204) “With Likely benign allele”, ClinVar (classified benign, reviewed by an expert panel (2013); submitters: benign by InSIGHT, and likely benign by Invitae, GeneDx, Laboratory for Molecular Medicine (Partners HealthCare Personalized Medicine), and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (2x), Insight Colon Cancer Gene Variant Database (13x as class 1), Zhejiang Colon Cancer Database (2x), Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database (14x), and was not identified in GeneInsight-COGR, Cosmic, MutDB, or UMD-LSDB. The variant was identified in control databases in 59 of 276412 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 59 of 18860 chromosomes (freq: 0.003), while not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr564 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the variant Ala impacting the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 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 this variant meets our laboratory's criteria to be classified as benign.

MSH2-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability <0.001

Hereditary nonpolyposis colorectal neoplasms Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 08, 2022

Fulgent Genetics, Fulgent Genetics

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	0.064
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Uncertain	0.13
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.35	T;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.025	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.1	L;.;.;.
PhyloP100		2.4
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.73	N;N;.;N
REVEL	Uncertain	0.49
Sift	Benign	0.81	T;T;.;T
Sift4G	Benign	0.78	T;T;.;T
Vest4		0.77
ClinPred		0.049	T
GERP RS		3.3
Varity_R		0.066
gMVP		0.32
Mutation Taster		=74/26	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: rs55778204; hg19: chr2-47698132;