5-80778719-G-A

Variant names:

• chr5-80778719-G-A
• rs866260675
• NM_002439.5:c.2319-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_002439.5(MSH3):​c.2319-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000705 in 1,418,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: MSH3 NM_002439.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.21
• Publications: 8 publications found

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

MSH3 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• MSH3-related attenuated familial adenomatous polyposis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.03427065 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9, offset of 41, new splice context is: tcactctccttttattgtAGaaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PP5: Variant 5-80778719-G-A is Pathogenic according to our data. Variant chr5-80778719-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 253325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. 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
	MSH3	NM_002439.5	MANE Select	c.2319-1G>A		splice_acceptor intron	N/A	NP_002430.3	P20585

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.2319-1G>A		splice_acceptor intron	N/A	ENSP00000265081.6	P20585
	MSH3	ENST00000658259.1		c.2151-1G>A		splice_acceptor intron	N/A	ENSP00000499617.1	A0A590UJW0
	MSH3	ENST00000667069.1		c.2124-1G>A		splice_acceptor intron	N/A	ENSP00000499502.1	A0A590UJN8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000705 AC: 10 AN: 1418538 Hom.: 0 Cov.: 27 AF XY: 0.00000988 AC XY: 7 AN XY: 708470

African (AFR) AF: 0.00 AC: 0 AN: 32562

American (AMR) AF: 0.0000224 AC: 1 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39460

South Asian (SAS) AF: 0.00 AC: 0 AN: 85440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00000839 AC: 9 AN: 1072478

Other (OTH) AF: 0.00 AC: 0 AN: 59000

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000734 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
2	-	-	Familial adenomatous polyposis 4 (2)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.78		Position offset: 1

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

Other links and lift over

dbSNP: rs866260675; hg19: chr5-80074538;