5-80670210-G-A

Position:

• chr5-80670210-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002439.5(MSH3):​c.693G>A​(p.Pro231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,613,768 control chromosomes in the GnomAD database, including 10,567 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P231P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1656 hom., cov: 33)
  • Exomes 𝑓: 0.081 (8911 hom.)
• Consequence: MSH3 NM_002439.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.01

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-80670210-G-A is Benign according to our data. Variant chr5-80670210-G-A is described in ClinVar as [Benign]. Clinvar id is 810935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80670210-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5	c.693G>A	p.Pro231=	synonymous_variant	4/24	ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.693G>A	p.Pro231=	synonymous_variant	4/24	1	NM_002439.5	P2
MSH3	ENST00000658259.1	c.525G>A	p.Pro175=	synonymous_variant	4/24			A2
MSH3	ENST00000667069.1	c.693G>A	p.Pro231=	synonymous_variant	4/22
MSH3	ENST00000670357.1	c.693G>A	p.Pro231=	synonymous_variant, NMD_transcript_variant	4/25

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18876 AN: 151932 Hom.: 1652 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.0835

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.0654

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0602

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.135 AC: 33835 AN: 251416 Hom.: 4092 AF XY: 0.121 AC XY: 16458 AN XY: 135886

Gnomad AFR exome AF: 0.190

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.326

Gnomad SAS exome AF: 0.0802

Gnomad FIN exome AF: 0.0703

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.0805 AC: 117705 AN: 1461718 Hom.: 8911 Cov.: 32 AF XY: 0.0794 AC XY: 57750 AN XY: 727172

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.137

Gnomad4 EAS exome AF: 0.364

Gnomad4 SAS exome AF: 0.0820

Gnomad4 FIN exome AF: 0.0712

Gnomad4 NFE exome AF: 0.0555

Gnomad4 OTH exome AF: 0.0948

GnomAD4 genome AF: 0.124 AC: 18900 AN: 152050 Hom.: 1656 Cov.: 33 AF XY: 0.127 AC XY: 9465 AN XY: 74336

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.335

Gnomad4 SAS AF: 0.0877

Gnomad4 FIN AF: 0.0654

Gnomad4 NFE AF: 0.0602

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0764 Hom.: 1692

Bravo AF: 0.145

Asia WGS AF: 0.179 AC: 620 AN: 3478

EpiCase AF: 0.0577

EpiControl AF: 0.0584

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 21128252, 27884173) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2018	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 28, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.5
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805355; hg19: chr5-79966029; COSMIC: COSV54159336;