rs26279

chr5-80873118-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002439.5(MSH3):c.3133G>A(p.Ala1045Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,610,178 control chromosomes in the GnomAD database, including 415,407 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1045I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.71 (37907 hom., cov: 32)
  • Exomes 𝑓: 0.72 (377500 hom.)
• Consequence: MSH3 NM_002439.5 missense, splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.92

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.821013E-7).
• BP6: Variant 5-80873118-G-A is Benign according to our data. Variant chr5-80873118-G-A is described in ClinVar as [Benign]. Clinvar id is 822964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-80873118-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH3	NM_002439.5	c.3133G>A	p.Ala1045Thr	missense_variant, splice_region_variant	23/24	ENST00000265081.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH3	ENST00000265081.7	c.3133G>A	p.Ala1045Thr	missense_variant, splice_region_variant	23/24	1	NM_002439.5	P2

Frequencies

GnomAD3 genomes AF: 0.706 AC: 107286 AN: 151968 Hom.: 37881 Cov.: 32

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.703

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.754

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.729

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.700

GnomAD3 exomes AF: 0.729 AC: 183208 AN: 251172 Hom.: 67007 AF XY: 0.730 AC XY: 99085 AN XY: 135756

Gnomad AFR exome AF: 0.664

Gnomad AMR exome AF: 0.756

Gnomad ASJ exome AF: 0.706

Gnomad EAS exome AF: 0.747

Gnomad SAS exome AF: 0.793

Gnomad FIN exome AF: 0.734

Gnomad NFE exome AF: 0.714

Gnomad OTH exome AF: 0.698

GnomAD4 exome AF: 0.719 AC: 1047769 AN: 1458094 Hom.: 377500 Cov.: 38 AF XY: 0.720 AC XY: 522185 AN XY: 725564

Gnomad4 AFR exome AF: 0.655

Gnomad4 AMR exome AF: 0.748

Gnomad4 ASJ exome AF: 0.703

Gnomad4 EAS exome AF: 0.753

Gnomad4 SAS exome AF: 0.795

Gnomad4 FIN exome AF: 0.729

Gnomad4 NFE exome AF: 0.713

Gnomad4 OTH exome AF: 0.712

GnomAD4 genome AF: 0.706 AC: 107363 AN: 152084 Hom.: 37907 Cov.: 32 AF XY: 0.707 AC XY: 52586 AN XY: 74342

Gnomad4 AFR AF: 0.668

Gnomad4 AMR AF: 0.703

Gnomad4 ASJ AF: 0.688

Gnomad4 EAS AF: 0.754

Gnomad4 SAS AF: 0.798

Gnomad4 FIN AF: 0.729

Gnomad4 NFE AF: 0.716

Gnomad4 OTH AF: 0.698

Alfa AF: 0.707 Hom.: 98298

Bravo AF: 0.700

TwinsUK AF: 0.719 AC: 2667

ALSPAC AF: 0.716 AC: 2759

ESP6500AA AF: 0.666 AC: 2934

ESP6500EA AF: 0.709 AC: 6101

ExAC AF: 0.730 AC: 88681

Asia WGS AF: 0.737 AC: 2563 AN: 3476

EpiCase AF: 0.692

EpiControl AF: 0.696

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	This variant is associated with the following publications: (PMID: 25966119, 17205513, 20708344) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 27, 2021	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	4.7
Dann	Benign	0.73
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.17	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.24	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.11
Sift	Benign	0.55	T
Sift4G	Benign	0.53	T
Polyphen		0.075	B
Vest4		0.018
MPC		0.026
ClinPred		0.0025	T
GERP RS		-2.5
Varity_R		0.025
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs26279; hg19: chr5-80168937; COSMIC: COSV54143807;