rs2303428

Variant names:

• chr2-47476361-T-C
• rs2303428
• NM_000251.3:c.2006-6T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47476361-T-C
• chr2-47476361-T-A
• chr2-47476361-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000251.3(MSH2):​c.2006-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,162 control chromosomes in the GnomAD database, including 10,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.089 (958 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9635 hom.)
• Consequence: MSH2 NM_000251.3 splice_region, intron
• Scores: Splicing: ADA: 0.9081
• Clinical Significance: Benign reviewed by expert panel B:27
• Conservation: PhyloP100: 1.45
• Publications: 85 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-47476361-T-C is Benign according to our data. Variant chr2-47476361-T-C is described in ClinVar as Benign. ClinVar VariationId is 36571.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

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.2006-6T>C		splice_region intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.2006-6T>C		splice_region intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.2006-6T>C		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.2006-6T>C		splice_region intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.2006-6T>C		splice_region intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.2057-6T>C		splice_region intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0890 AC: 13536 AN: 152086 Hom.: 960 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0894

Gnomad EAS AF: 0.341

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.0947

GnomAD2 exomes AF: 0.115 AC: 28906 AN: 251186 AF XY: 0.116

Gnomad AFR exome AF: 0.0214

Gnomad AMR exome AF: 0.0793

Gnomad ASJ exome AF: 0.0949

Gnomad EAS exome AF: 0.355

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.0995

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.106 AC: 155365 AN: 1460956 Hom.: 9635 Cov.: 32 AF XY: 0.107 AC XY: 77935 AN XY: 726842

African (AFR) AF: 0.0214 AC: 716 AN: 33470

American (AMR) AF: 0.0806 AC: 3606 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0968 AC: 2529 AN: 26126

East Asian (EAS) AF: 0.312 AC: 12379 AN: 39680

South Asian (SAS) AF: 0.133 AC: 11469 AN: 86244

European-Finnish (FIN) AF: 0.111 AC: 5921 AN: 53388

Middle Eastern (MID) AF: 0.0988 AC: 570 AN: 5768

European-Non Finnish (NFE) AF: 0.100 AC: 111239 AN: 1111206

Other (OTH) AF: 0.115 AC: 6936 AN: 60358

GnomAD4 genome AF: 0.0889 AC: 13534 AN: 152206 Hom.: 958 Cov.: 32 AF XY: 0.0919 AC XY: 6841 AN XY: 74410

African (AFR) AF: 0.0260 AC: 1080 AN: 41542

American (AMR) AF: 0.103 AC: 1580 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0894 AC: 310 AN: 3468

East Asian (EAS) AF: 0.340 AC: 1760 AN: 5172

South Asian (SAS) AF: 0.143 AC: 690 AN: 4822

European-Finnish (FIN) AF: 0.100 AC: 1064 AN: 10598

Middle Eastern (MID) AF: 0.0479 AC: 14 AN: 292

European-Non Finnish (NFE) AF: 0.100 AC: 6810 AN: 67998

Other (OTH) AF: 0.0961 AC: 203 AN: 2112

Alfa AF: 0.0790 Hom.: 348

Bravo AF: 0.0840

Asia WGS AF: 0.216 AC: 750 AN: 3478

EpiCase AF: 0.100

EpiControl AF: 0.0981

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	7	Lynch syndrome 1 (7)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	Lynch syndrome (3)
-	-	3	not provided (3)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Mismatch repair cancer syndrome 1 (1)
-	-	1	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.85
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.020		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: rs2303428; hg19: chr2-47703500; COSMIC: COSV51876931; COSMIC: COSV51876931;