chr2-47466813-G-C

Variant names:

• chr2-47466813-G-C
• rs267607972
• NM_000251.3:c.1661+5G>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.1661+5G>C variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000685 in 1,459,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.12
• Publications: 3 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47466813-G-C is Pathogenic according to our data. Variant chr2-47466813-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 90721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1661+5G>C		splice_region intron	N/A	NP_000242.1
	MSH2	NM_001406674.1		c.1661+5G>C		splice_region intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1661+5G>C		splice_region intron	N/A	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1661+5G>C		splice_region intron	N/A	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.1661+5G>C		splice_region intron	N/A	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.1661+5G>C		splice_region intron	N/A	ENSP00000495455.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250972 AF XY: 0.00000737

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459884 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726360

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110576

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Aug 06, 2024

Department of Human Genetics, Hannover Medical School

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12362047, 33259954, 27601186]. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 32849802, 12362047].

not provided Pathogenic:2

Mar 08, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12362047, 25081409, 27601186, 33259954, 32849802, 36425062, 16451135, 11879922)

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2: PVS1, PM2, PS4:Moderate

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 10 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs267607972, gnomAD 0.0009%). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 12362047, 25081409; Invitae). ClinVar contains an entry for this variant (Variation ID: 90721). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 and introduces a premature termination codon (PMID: 12362047, 32849802; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Jun 09, 2020

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1661+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 10 in the MSH2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been reported in a Polish Lynch syndrome family and was shown to cause skipping of exon 10 leading to the creation of a new stop codon (Kurzawski G et al. J. Med. Genet., 2002 Oct;39:E65). This alteration has also been identified in a cohort of Swedish Lynch syndrome families (Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835) and in an individual with endometrial cancer whose tumor showed microsatellite instability and loss of MSH2 protein staining via immunohistochemisty (Ferguson SE et al. Cancer, 2014 Dec;120:3932-9). In addition, this allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Endometrial carcinoma Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MSH2 c.1661+5G>C variant was identified in 3 out of 832 proband chromosomes (frequency 0.004) in Polish individuals having met Amsterdam II criteria or suspected of having Lynch Syndrome; and Canadian individuals with endometrial cancer (Kurzawski 2002, Kurzawski 2006, Ferguson 2014). The variant was also identified in dbSNP (ID: rs267607972) as “With Uncertain significance allele”, Clinvitae database (classification uncertain significance), InSiGHT Colon Cancer Gene Variant Database (LOVD) (4X, as unknown pathogenicity), the ClinVar database (classification uncertain significance, reviewed by an expert panel), 1000 Genomes Project in 1 of 125000 chromosomes (frequency: 0.000008), and the Exome Aggregation Consortium database (March 14, 2016) in 1 of 121162 chromosomes (freq. 000008) in a population of European (Non-Finnish) individuals in 1 of 66680 chromosomes (freq. 0.000015), and none from South Asian, Latino, African, East Asian, European (Finnish) or Other populations. The c.1661+5G>C variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. The nature of the previously unreported c.1661+5G>C variant was confirmed at the RNA level (from fresh lymphocytes) with the identification of an aberrant transcript which caused skipping of exon 10 and creation of a downstream stop codon (p.Gly504_Ser554>AlafsX3, Kurzawski 2002, Kurzawski 2006). The variant was also identified by our laboratory in 2 individuals with endometrial cancer (one with reported tumour IHC deficiency) and was not identified by familial variant testing for eight reportedly unaffected individuals from 3 separate families. In summary, based on the above information, this variant is classified as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.97
PhyloP100		5.1
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs267607972; hg19: chr2-47693952;