2-47482929-C-T

Variant names:

• chr2-47482929-C-T
• rs551060742
• NM_000251.3:c.2785C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000251.3(MSH2):​c.2785C>T​(p.Arg929*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,611,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:6 B:9
• Conservation: PhyloP100: 2.34
• Publications: 24 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 2 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.00713 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2785C>T	p.Arg929*	stop_gained	Exon 16 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2785C>T	p.Arg929*	stop_gained	Exon 16 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151974 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000845 AC: 21 AN: 248568 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000927

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1459282 Hom.: 0 Cov.: 31 AF XY: 0.0000262 AC XY: 19 AN XY: 725822

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.000430 AC: 17 AN: 39556

South Asian (SAS) AF: 0.0000467 AC: 4 AN: 85718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.000376 AC: 2 AN: 5324

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111120

Other (OTH) AF: 0.0000663 AC: 4 AN: 60288

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152092 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74364

African (AFR) AF: 0.0000724 AC: 3 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000519 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000742 AC: 9

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:6 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Uncertain:2 Benign:2

Aug 31, 2016

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. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2025

Molecular Pathology, Peter Maccallum Cancer Centre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

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 at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

May 27, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 28, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 14, 2021

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. -

Lynch syndrome Uncertain:1 Benign:1

Jun 21, 2019

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

Nonsense variant after codon 888 in MSH2 = VUS -

May 02, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria has been used: BS1; BP5; PVS1_MOD -

not provided Uncertain:1 Benign:1

Apr 06, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation as the last 6 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Occurred in cis with a nonsense variant in the MSH6 gene in eight unrelated Portuguese Lynch syndrome families; tumor immunohistochemistry (IHC) revealed normal MSH2 expression in 5/8 cases and absence of MSH6 protein in 7/7 cases with interpretable data (PMID: 26446363); Observed in two individuals with colorectal cancer, co-occurring with a pathogenic MSH2 founder pathogenic variant in one individual, as well as in individuals with breast and/or ovarian cancer (PMID: 12624141, 21681552, 24240112, 26824983, 28050010, 28724667, 32068069, 35264596, 35449176, 35534704); This variant is associated with the following publications: (PMID: 12624141, 28127413, 28724667, 21681552, 24344984, 24240112, 26824983, 28874130, 28332257, 29752822, 29506494, 28050010, 9774676, 18822302, 21120944, 27873144, 33015532, 31569399, 26689913, 32029870, 31207149, 35264596, 35980532, 32068069, 35534704, 28514183, 26446363, 35449176) -

not specified Benign:2

Dec 18, 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.2785C>T (p.Arg929X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. This variant leads to encoding a protein that is 6 AA shorter and without interruption of any known functional domain (Pinto_MSH2_JHG_2016). Truncations downstream of this position have not been classified as pathogenic by our laboratory or in ClinVar. The variant allele was found at a frequency of 8.4e-05 in 248768 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.64 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2785C>T has been reported in the literature in individuals affected with colorectal cancer, lynch syndrome, breast cancer, and prostate cancer (examples: Parc_2003, Valentin_2011, Feliubadalo_2017, Lin_2016, Pennington_2013, Pinto_2016, Lu_2015, Sun_2017, Li_2019, Kwong_2020, Fang_2023). However, many of these cases had one or more co-occurrences with other pathogenic variants (MSH2 c. 942+3A>T; MSH6 c.1030C>T, p.Gln344Ter; BRCA1 c.190T>C, p.C64R; BRCA2 c.9090dupA, p.T3030fs; BRCA1 c.4327C>T, p.R1443X) (Valentin_2011, Pinto_2016, Sun2017 and Li_2019 ), providing supporting evidence for a benign role. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 16451135, 28127413, 24344984, 36522531, 28050010, 32068069, 29752822, 26824983, 26689913, 12624141, 24240112, 26446363, 28724667, 21681552). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments - pathogenic (n=1), likely benign/benign (n=4) and VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Carcinoma of colon Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Arg989X variant was identified in 10 of 474 proband chromosomes (frequency: 0.021) from South American and Portugese individuals or families with Lynch syndrome, meeting Amsterdam or Bethesda criteria, and was not identified in 200 control chromosomes from healthy individuals (Valentin 2011, Pinto 2015). However eight of the nine patients identified by Pinto et al. were also found to have a co-occurring pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), five of the eight double mutant tumors had normal MSH2 expression and the ninth patient lacked a family history of colon cancer. The patient identified by Valentin et al. was also found to have a co-occurring pathogenic mutation, MSH2: c.942+3A>T (Valentin 2011). The variant was also identified in dbSNP (ID: rs551060742) “With pathogenic allele”, 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002), the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 9 of 113840 chromosomes (frequency: 0.00008) (or 9 individuals from a population of 8454 East Asian individuals, frequency 0.001); Clinvitae database (classification pathogenic), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (classified as pathogenic, and reviewed by an expert panel; being classified as pathogenic by InSight, and uncertain significance by Invitae), and UMD (9x with a “causal” classification). The above classifications were only updated as recently as 2014. The variant was also identified by our laboratory in 1 individual of Portugese background, with colon cancer, co-occurring with a pathogenic MSH6 mutation (c.1030C>T, p.Gln344X), as seen in the Portugese families from Pinto’s study (Pinto_2015_26446363). The p.Arg989X variant leads to a premature stop codon at position 989, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. However, the p.Arg989X encodes a protein 6 amino acids short of the wildtype transcript, without interruption of any known functional domain. Notably, this mutation occurs in the last exon of the MSH2 gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. However, due to conflicting interpretations above, this variant is classified as a variant of unknown significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Jan 08, 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
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.35
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		2.3
Vest4		0.75
GERP RS		2.6
Mutation Taster		=4/196	disease causing

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: rs551060742; hg19: chr2-47710068; COSMIC: COSV51878909;