rs26279

Variant names:

• chr5-80873118-G-A
• rs26279
• NM_002439.5:c.3133G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-80873118-G-A
• chr5-80873118-G-T

Variant summary

Our verdict is Benign. The variant received -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. 16/21 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. 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
• Publications: 117 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 822964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.3133G>A	p.Ala1045Thr	missense_variant, splice_region_variant	Exon 23 of 24	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.3133G>A	p.Ala1045Thr	missense_variant, splice_region_variant	Exon 23 of 24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.2965G>A	p.Ala989Thr	missense_variant, splice_region_variant	Exon 23 of 24			ENSP00000499617.1
MSH3	ENST00000667069.1	c.2938G>A	p.Ala980Thr	missense_variant, splice_region_variant	Exon 21 of 22			ENSP00000499502.1
MSH3	ENST00000670357.1	n.*457G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 24 of 25			ENSP00000499791.1
MSH3	ENST00000670357.1	n.*457G>A		3_prime_UTR_variant	Exon 24 of 25			ENSP00000499791.1

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

GnomAD2 exomes AF: 0.729 AC: 183208 AN: 251172 AF XY: 0.730

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 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

African (AFR) AF: 0.655 AC: 21864 AN: 33380

American (AMR) AF: 0.748 AC: 33415 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.703 AC: 18336 AN: 26096

East Asian (EAS) AF: 0.753 AC: 29816 AN: 39610

South Asian (SAS) AF: 0.795 AC: 68513 AN: 86172

European-Finnish (FIN) AF: 0.729 AC: 38957 AN: 53404

Middle Eastern (MID) AF: 0.632 AC: 3635 AN: 5756

European-Non Finnish (NFE) AF: 0.713 AC: 790324 AN: 1108720

Other (OTH) AF: 0.712 AC: 42909 AN: 60256

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

African (AFR) AF: 0.668 AC: 27688 AN: 41454

American (AMR) AF: 0.703 AC: 10736 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2385 AN: 3468

East Asian (EAS) AF: 0.754 AC: 3911 AN: 5184

South Asian (SAS) AF: 0.798 AC: 3844 AN: 4818

European-Finnish (FIN) AF: 0.729 AC: 7700 AN: 10556

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48703 AN: 68004

Other (OTH) AF: 0.698 AC: 1475 AN: 2112

Alfa AF: 0.708 Hom.: 185427

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

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25966119, 17205513, 20708344) -

Hereditary cancer-predisposing syndrome Benign:2

Feb 27, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Sep 10, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		1.9
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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs26279; hg19: chr5-80168937; COSMIC: COSV54143807;