chr5-80746456-T-G

Variant names:

• chr5-80746456-T-G
• rs863221
• NM_002439.5:c.1763+1841T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002439.5(MSH3):​c.1763+1841T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 490,212 control chromosomes in the GnomAD database, including 34,190 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9158 hom., cov: 32)
  • Exomes 𝑓: 0.38 (25032 hom.)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• Publications: 11 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• MSH3-related attenuated familial adenomatous polyposis

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000248967 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.1763+1841T>G		intron_variant	Intron 12 of 23	ENST00000265081.7	NP_002430.3
LOC124901016		n.80746456T>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.1763+1841T>G		intron_variant	Intron 12 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.1595+1841T>G		intron_variant	Intron 12 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.1569-15090T>G		intron_variant	Intron 10 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.1763+1841T>G		intron_variant	Intron 12 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51280 AN: 151912 Hom.: 9159 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.453

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.415

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.394

Gnomad OTH AF: 0.326

GnomAD4 exome AF: 0.380 AC: 128486 AN: 338182 Hom.: 25032 Cov.: 0 AF XY: 0.384 AC XY: 74607 AN XY: 194140

African (AFR) AF: 0.194 AC: 1787 AN: 9218

American (AMR) AF: 0.312 AC: 9687 AN: 31064

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 3740 AN: 10846

East Asian (EAS) AF: 0.363 AC: 4312 AN: 11878

South Asian (SAS) AF: 0.411 AC: 25326 AN: 61594

European-Finnish (FIN) AF: 0.429 AC: 8880 AN: 20700

Middle Eastern (MID) AF: 0.307 AC: 348 AN: 1132

European-Non Finnish (NFE) AF: 0.390 AC: 68846 AN: 176596

Other (OTH) AF: 0.367 AC: 5560 AN: 15154

GnomAD4 genome AF: 0.337 AC: 51303 AN: 152030 Hom.: 9158 Cov.: 32 AF XY: 0.342 AC XY: 25388 AN XY: 74280

African (AFR) AF: 0.203 AC: 8407 AN: 41504

American (AMR) AF: 0.341 AC: 5206 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1153 AN: 3470

East Asian (EAS) AF: 0.361 AC: 1854 AN: 5140

South Asian (SAS) AF: 0.415 AC: 1993 AN: 4806

European-Finnish (FIN) AF: 0.449 AC: 4752 AN: 10572

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.394 AC: 26745 AN: 67958

Other (OTH) AF: 0.327 AC: 690 AN: 2112

Alfa AF: 0.365 Hom.: 1321

Bravo AF: 0.318

Asia WGS AF: 0.391 AC: 1361 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.82
DANN	Benign	0.73
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs863221; hg19: chr5-80042275; COSMIC: COSV54153093;