2-47482797-C-T

Variant names:

• chr2-47482797-C-T
• rs63750808
• NM_000251.3:c.2653C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_000251.3(MSH2):​c.2653C>T​(p.Gln885*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: "SCV000322359: The disrupted region at the end of the gene contains the helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). Additionally, Wielders et al. (2017) found that MSH2 variants lacking the c-terminus severely destabilize MSH2/MSH6 interaction and result in increased microsatellite instability.". Synonymous variant affecting the same amino acid position (i.e. Q885Q) has been classified as Likely benign. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 1.91
• Publications: 7 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.

• 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. There are 12 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322359: The disrupted region at the end of the gene contains the helix-turn-helix domain and the region of interaction with MSH6 and MSH3 (Guerrette 1998, Lutzen 2008, Kansikas 2011). Additionally, Wielders et al. (2017) found that MSH2 variants lacking the c-terminus severely destabilize MSH2/MSH6 interaction and result in increased microsatellite instability.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-47482797-C-T is Pathogenic according to our data. Variant chr2-47482797-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 91033.Status of the report is reviewed_by_expert_panel, 3 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.2653C>T	p.Gln885*	stop_gained	Exon 16 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406638.1		c.2692C>T	p.Gln898*	stop_gained	Exon 17 of 18	NP_001393567.1
	MSH2	NM_001406641.1		c.2653C>T	p.Gln885*	stop_gained	Exon 16 of 17	NP_001393570.1	P43246-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2653C>T	p.Gln885*	stop_gained	Exon 16 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.2634+1926C>T		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.2704C>T	p.Gln902*	stop_gained	Exon 17 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Lynch syndrome 1 (3)
3	-	-	not provided (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colon cancer (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		1.9
Vest4		0.93
GERP RS		5.5
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)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: -18

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

Other links and lift over

dbSNP: rs63750808; hg19: chr2-47709936;