rs587782759

Variant names:

• chr2-47403307-G-A
• rs587782759
• NM_000251.3:c.116G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47403307-G-A
• chr2-47403307-G-C
• chr2-47403307-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP3_Moderate BP6

The NM_000251.3(MSH2):​c.116G>A​(p.Arg39Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R39L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.15
• Publications: 8 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: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911
• BP6: Variant 2-47403307-G-A is Benign according to our data. Variant chr2-47403307-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 850879.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.116G>A	p.Arg39Gln	missense	Exon 1 of 16	NP_000242.1
	MSH2	NM_001406674.1		c.116G>A	p.Arg39Gln	missense	Exon 1 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.116G>A	p.Arg39Gln	missense	Exon 1 of 18	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.116G>A	p.Arg39Gln	missense	Exon 1 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.116G>A	p.Arg39Gln	missense	Exon 1 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.116G>A	p.Arg39Gln	missense	Exon 1 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 227056 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451802 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721290

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 42728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25738

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.00 AC: 0 AN: 84146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109142

Other (OTH) AF: 0.00 AC: 0 AN: 60022

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.98	D
Vest4		0.74
MutPred		0.72		Loss of stability (P = 0.194)
MVP		0.97
MPC		0.031
ClinPred		0.99	D
GERP RS		5.7
PromoterAI		0.0049	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.87
gMVP		0.70
Mutation Taster		=51/49	polymorphism

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: rs587782759; hg19: chr2-47630446;