rs6544991

Variant names:

• chr2-47485641-A-C
• rs6544991
• ENST00000406134.5:c.2634+4770A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47485641-A-C
• chr2-47485641-A-G
• chr2-47485641-A-T

Variant summary

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

The NM_001406674.1(MSH2):​c.2634+4770A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 152,124 control chromosomes in the GnomAD database, including 3,692 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 0.21 (3692 hom., cov: 32)
• Consequence: MSH2 NM_001406674.1 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 1.70
• Publications: 19 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=-0.83).
• BP6: Variant 2-47485641-A-C is Benign according to our data. Variant chr2-47485641-A-C is described in ClinVar as Benign. ClinVar VariationId is 90481.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406674.1. 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_001406674.1		c.2634+4770A>C		intron	N/A	NP_001393603.1
	MSH2	NM_001406631.1		c.2634+4770A>C		intron	N/A	NP_001393560.1
	MSH2	NM_001406632.1		c.2634+4770A>C		intron	N/A	NP_001393561.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000406134.5	TSL:1	c.2634+4770A>C		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000910408.1		c.*23+2669A>C		intron	N/A	ENSP00000580467.1
	MSH2	ENST00000645506.1		c.2634+4770A>C		intron	N/A	ENSP00000495455.1	A0A2R8Y6P0

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32447 AN: 152006 Hom.: 3693 Cov.: 32

Gnomad AFR AF: 0.245

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.194

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.213 AC: 32466 AN: 152124 Hom.: 3692 Cov.: 32 AF XY: 0.218 AC XY: 16190 AN XY: 74382

African (AFR) AF: 0.245 AC: 10160 AN: 41486

American (AMR) AF: 0.212 AC: 3247 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1742 AN: 5184

South Asian (SAS) AF: 0.195 AC: 939 AN: 4812

European-Finnish (FIN) AF: 0.304 AC: 3212 AN: 10574

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12046 AN: 68000

Other (OTH) AF: 0.194 AC: 410 AN: 2112

Alfa AF: 0.176 Hom.: 3287

Bravo AF: 0.209

Asia WGS AF: 0.264 AC: 917 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	-0.83
CADD	Benign	6.4
DANN	Benign	0.63
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs6544991; hg19: chr2-47712780;