chr2-47403209-G-T

Variant names:

• chr2-47403209-G-T
• rs146017810
• NM_000251.3:c.18G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001406654.1(MSH2):​c.-323G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_001406654.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.797
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3246508).
• BP6: Variant 2-47403209-G-T is Benign according to our data. Variant chr2-47403209-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1367434.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406654.1. 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_000251.3	MANE Select	c.18G>T	p.Lys6Asn	missense	Exon 1 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406654.1		c.-323G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001393583.1
	MSH2	NM_001406656.1		c.-978G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001393585.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.18G>T	p.Lys6Asn	missense	Exon 1 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.18G>T	p.Lys6Asn	missense	Exon 1 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.18G>T	p.Lys6Asn	missense	Exon 1 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447150 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718642

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 42352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.00 AC: 0 AN: 39186

South Asian (SAS) AF: 0.00 AC: 0 AN: 83874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106368

Other (OTH) AF: 0.00 AC: 0 AN: 59820

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	0.79
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	-0.061
Eigen_PC	Benign	0.0073
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.8	L
PhyloP100		0.80
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.94	N
REVEL	Uncertain	0.47
Sift	Benign	0.32	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.58
MutPred		0.36		Loss of ubiquitination at K6 (P = 0.0074)
MVP		0.89
MPC		0.0062
ClinPred		0.56	D
GERP RS		2.7
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.48
gMVP		0.42
Mutation Taster		=87/13	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: rs146017810; hg19: chr2-47630348;