2-47403261-C-T

Variant names:

• chr2-47403261-C-T
• rs587779976
• NM_000251.3:c.70C>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000251.3(MSH2):​c.70C>T​(p.Gln24*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,728 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q24Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4 B:1
• Conservation: PhyloP100: 1.91
• Publications: 6 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

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 1832 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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.70C>T	p.Gln24*	stop_gained	Exon 1 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.70C>T	p.Gln24*	stop_gained	Exon 1 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.70C>T	p.Gln24*	stop_gained	Exon 1 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.70C>T	p.Gln24*	stop_gained	Exon 1 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.70C>T	p.Gln24*	stop_gained	Exon 1 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.70C>T	p.Gln24*	stop_gained	Exon 1 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000454 AC: 1 AN: 220192 AF XY: 0.00000832

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447728 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719042

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.0000238 AC: 1 AN: 41980

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 39184

South Asian (SAS) AF: 0.00 AC: 0 AN: 83804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5606

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107018

Other (OTH) AF: 0.00 AC: 0 AN: 59876

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000100 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		1.9
Vest4		0.67
GERP RS		3.5
PromoterAI		-0.0096	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs587779976; hg19: chr2-47630400; COSMIC: COSV109407782;