5-80654962-A-T

Variant names:

• chr5-80654962-A-T
• rs1650697
• NM_002439.5:c.235A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002439.5(MSH3):​c.235A>T​(p.Ile79Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I79V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH3 NM_002439.5 missense, splice_region
• Scores: Splicing: ADA: 0.04863
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.243

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]

DHFR (HGNC:2861): (dihydrofolate reductase) Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07459539).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.235A>T	p.Ile79Leu	missense_variant, splice_region_variant	Exon 1 of 24	ENST00000265081.7	NP_002430.3
DHFR	NM_000791.4	c.-473T>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000439211.7	NP_000782.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.235A>T	p.Ile79Leu	missense_variant, splice_region_variant	Exon 1 of 24	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000667069.1	c.235A>T	p.Ile79Leu	missense_variant, splice_region_variant	Exon 1 of 22			ENSP00000499502.1
DHFR	ENST00000439211.7	c.-473T>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_000791.4	ENSP00000396308.2
MSH3	ENST00000670357.1	n.235A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 25			ENSP00000499791.1
MSH3	ENST00000658259.1	c.-232A>T		upstream_gene_variant				ENSP00000499617.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1325022 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 653096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Sep 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces isoleucine with leucine at codon 79 of the MSH3 protein (p.Ile79Leu). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and leucine. -

Jun 25, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I79L variant (also known as c.235A>T), located in coding exon 1 of the MSH3 gene, results from an A to T substitution at nucleotide position 235. The isoleucine at codon 79 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	11
DANN	Benign	0.67
DEOGEN2	Benign	0.096	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.19	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.22
Sift	Benign	0.16	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.10		Gain of glycosylation at P77 (P = 0.1164);
MVP		0.60
MPC		0.026
ClinPred		0.35	T
GERP RS		-4.5
Varity_R		0.068
gMVP		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.049
dbscSNV1_RF	Benign	0.44
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs1650697; hg19: chr5-79950781;