2-47414416-C-T

Variant names:

• chr2-47414416-C-T
• rs1114167845
• NM_000251.3:c.940C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PVS1 PP3 PP5_Very_Strong

The NM_000251.3(MSH2):​c.940C>T​(p.Gln314*) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q314Q) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000022 (0 hom., cov: 14)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.59
• Publications: 8 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 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-47414416-C-T is Pathogenic according to our data. Variant chr2-47414416-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 428507.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.940C>T	p.Gln314*	stop_gained splice_region	Exon 5 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.940C>T	p.Gln314*	stop_gained splice_region	Exon 5 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.940C>T	p.Gln314*	stop_gained splice_region	Exon 5 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.940C>T	p.Gln314*	stop_gained splice_region	Exon 5 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.940C>T	p.Gln314*	stop_gained splice_region	Exon 5 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.991C>T	p.Gln331*	stop_gained splice_region	Exon 6 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0000221 AC: 1 AN: 45216 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.00

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: 0.0000373

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 439306 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 230810

African (AFR) AF: 0.00 AC: 0 AN: 10912

American (AMR) AF: 0.00 AC: 0 AN: 19060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10212

East Asian (EAS) AF: 0.00 AC: 0 AN: 13868

South Asian (SAS) AF: 0.00 AC: 0 AN: 42492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1326

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 298318

Other (OTH) AF: 0.00 AC: 0 AN: 18004

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000221 AC: 1 AN: 45216 Hom.: 0 Cov.: 14 AF XY: 0.00 AC XY: 0 AN XY: 19862

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

African (AFR) AF: 0.00 AC: 0 AN: 10942

American (AMR) AF: 0.00 AC: 0 AN: 2326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1532

East Asian (EAS) AF: 0.00 AC: 0 AN: 1426

South Asian (SAS) AF: 0.00 AC: 0 AN: 892

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.0000373 AC: 1 AN: 26840

Other (OTH) AF: 0.00 AC: 0 AN: 454

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Lynch syndrome 1 (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	45
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.6
Vest4		0.98
GERP RS		5.0
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
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.030		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: rs1114167845; hg19: chr2-47641555; COSMIC: COSV51876473;