rs3771281

Variant names:

• chr2-47465142-C-T
• rs3771281
• NM_000251.3:c.1511-1516C>T

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.1511-1516C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 151,978 control chromosomes in the GnomAD database, including 19,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.48 (19456 hom., cov: 32)
• Consequence: MSH2 NM_000251.3 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -0.436
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 2-47465142-C-T is Benign according to our data. Variant chr2-47465142-C-T is described in ClinVar as Benign. ClinVar VariationId is 90687.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 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.1511-1516C>T		intron	N/A	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1511-1516C>T		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.1511-1516C>T		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.1511-1516C>T		intron	N/A	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1511-1516C>T		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1562-1516C>T		intron	N/A	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.484 AC: 73498 AN: 151858 Hom.: 19417 Cov.: 32

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.659

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.498

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.451

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.484 AC: 73598 AN: 151978 Hom.: 19456 Cov.: 32 AF XY: 0.486 AC XY: 36110 AN XY: 74276

African (AFR) AF: 0.688 AC: 28523 AN: 41442

American (AMR) AF: 0.395 AC: 6028 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1146 AN: 3464

East Asian (EAS) AF: 0.658 AC: 3408 AN: 5178

South Asian (SAS) AF: 0.431 AC: 2070 AN: 4808

European-Finnish (FIN) AF: 0.498 AC: 5252 AN: 10550

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.377 AC: 25647 AN: 67952

Other (OTH) AF: 0.451 AC: 953 AN: 2114

Alfa AF: 0.405 Hom.: 7621

Bravo AF: 0.485

Asia WGS AF: 0.551 AC: 1913 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.55
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

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: rs3771281; hg19: chr2-47692281;