chr2-47429812-C-T

Variant names:

• chr2-47429812-C-T
• rs63749849
• NM_000251.3:c.1147C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_001406658.1(MSH2):​c.-210C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000137 in 1,461,826 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002761478: The Arg383* variant has been identified in numerous patients with Lynch syndrome and a function study has shown that the variant results in loss of the allele through nonsense mediated decay." and additional evidence is available in ClinVar. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_001406658.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic reviewed by expert panel P:24 U:1
• Conservation: PhyloP100: 4.30
• Publications: 31 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002761478: The Arg383* variant has been identified in numerous patients with Lynch syndrome and a function study has shown that the variant results in loss of the allele through nonsense mediated decay.; SCV001360858: Banville et al (2006) showed loss of expression of MSH2 and MSH6 in tumor samples from a patient carrying this variant. Thompson et al (2014) reported a truncated polypeptide of MSH2 following protein truncation testing performed on patient RNA.
• PM2: Very rare variant in population databases, with high coverage
• PP3: BayesDel_addAF computational evidence supports a deleterious effect, 0.625
• PP5: Variant 2-47429812-C-T is Pathogenic according to our data. Variant chr2-47429812-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 90554.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406658.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1147C>T	p.Arg383*	stop_gained	Exon 7 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406658.1		c.-210C>T		5_prime_UTR_premature_start_codon_gain	Exon 7 of 16	NP_001393587.1
	MSH2	NM_001406659.1		c.-210C>T		5_prime_UTR_premature_start_codon_gain	Exon 8 of 17	NP_001393588.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1147C>T	p.Arg383*	stop_gained	Exon 7 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1147C>T	p.Arg383*	stop_gained	Exon 7 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1198C>T	p.Arg400*	stop_gained	Exon 8 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461826 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727218

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	1	-	not provided (9)
4	-	-	Lynch syndrome 1 (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
2	-	-	Hereditary nonpolyposis colon cancer (2)
2	-	-	Lynch syndrome (2)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Inherited MMR deficiency (Lynch syndrome) (1)
1	-	-	Lynch-like syndrome (1)
1	-	-	MSH2-related disorder (1)
1	-	-	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 (1)
1	-	-	Rhabdomyosarcoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		4.3
Vest4		0.92
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs63749849; hg19: chr2-47656951; COSMIC: COSV51878760;