chr2-47471040-A-G

Variant names:

• chr2-47471040-A-G
• rs61756467
• NM_000251.3:c.1737A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000251.3(MSH2):​c.1737A>G​(p.Lys579Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,550,890 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:29
• Conservation: PhyloP100: 1.47
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 2-47471040-A-G is Benign according to our data. Variant chr2-47471040-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 36570.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00148 (2071/1398534) while in subpopulation MID AF = 0.0102 (56/5504). AF 95% confidence interval is 0.00805. There are 6 homozygotes in GnomAdExome4. There are 1103 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

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.1737A>G	p.Lys579Lys	synonymous	Exon 11 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1737A>G	p.Lys579Lys	synonymous	Exon 11 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1737A>G	p.Lys579Lys	synonymous	Exon 11 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.1737A>G	p.Lys579Lys	synonymous	Exon 11 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1737A>G	p.Lys579Lys	synonymous	Exon 11 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1788A>G	p.Lys596Lys	synonymous	Exon 12 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00215 AC: 540 AN: 250870 AF XY: 0.00230

Gnomad AFR exome AF: 0.000744

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00924

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00148 AC: 2071 AN: 1398534 Hom.: 6 Cov.: 24 AF XY: 0.00158 AC XY: 1103 AN XY: 699520

African (AFR) AF: 0.000776 AC: 25 AN: 32228

American (AMR) AF: 0.00193 AC: 86 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.00884 AC: 227 AN: 25678

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39278

South Asian (SAS) AF: 0.00273 AC: 232 AN: 84836

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53344

Middle Eastern (MID) AF: 0.0102 AC: 56 AN: 5504

European-Non Finnish (NFE) AF: 0.00112 AC: 1180 AN: 1054810

Other (OTH) AF: 0.00261 AC: 152 AN: 58238

GnomAD4 genome AF: 0.00148 AC: 226 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74514

African (AFR) AF: 0.000697 AC: 29 AN: 41592

American (AMR) AF: 0.00111 AC: 17 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4824

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10628

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00143 AC: 97 AN: 68030

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00149

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Lynch syndrome 1 (6)
-	-	6	not provided (6)
-	-	6	not specified (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	2	Lynch syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	MSH2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.0
DANN	Benign	0.71
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs61756467; hg19: chr2-47698179;