NM_000251.3:c.942+5A>G

Variant names:

• chr2-47414423-A-G
• rs769242733
• NM_000251.3:c.942+5A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Moderate BP6_Very_Strong

The NM_000251.3(MSH2):​c.942+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 171,552 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000011 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: MSH2 NM_000251.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001251
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.308
• Publications: 0 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: Benign. The variant received -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-47414423-A-G is Benign according to our data. Variant chr2-47414423-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 984501.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.942+5A>G		splice_region intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.942+5A>G		splice_region intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.942+5A>G		splice_region intron	N/A	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.942+5A>G		splice_region intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.942+5A>G		splice_region intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.993+5A>G		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0000107 AC: 1 AN: 93458 Hom.: 0 Cov.: 25

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: 0.0000210

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0172 AC: 804 AN: 46704 AF XY: 0.0171

Gnomad AFR exome AF: 0.0376

Gnomad AMR exome AF: 0.0320

Gnomad ASJ exome AF: 0.0184

Gnomad EAS exome AF: 0.0335

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00892

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0000256 AC: 2 AN: 78094 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 38004

African (AFR) AF: 0.00 AC: 0 AN: 1482

American (AMR) AF: 0.00 AC: 0 AN: 1808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1480

East Asian (EAS) AF: 0.00 AC: 0 AN: 456

South Asian (SAS) AF: 0.00 AC: 0 AN: 4240

European-Finnish (FIN) AF: 0.000204 AC: 1 AN: 4908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.0000164 AC: 1 AN: 60800

Other (OTH) AF: 0.00 AC: 0 AN: 2644

GnomAD4 genome AF: 0.0000107 AC: 1 AN: 93458 Hom.: 0 Cov.: 25 AF XY: 0.0000222 AC XY: 1 AN XY: 45052

⚠️ 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: 19254

American (AMR) AF: 0.00 AC: 0 AN: 10070

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2400

East Asian (EAS) AF: 0.00 AC: 0 AN: 3446

South Asian (SAS) AF: 0.00 AC: 0 AN: 2996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 182

European-Non Finnish (NFE) AF: 0.0000210 AC: 1 AN: 47732

Other (OTH) AF: 0.00 AC: 0 AN: 1330

⚠️ 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: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		0.31
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.020
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: rs769242733; hg19: chr2-47641562;