rs376183465
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BS1_Supporting
The NM_004448.4(ERBB2):c.734C>T(p.Thr245Met) variant causes a missense change. The variant allele was found at a frequency of 0.000109 in 1,612,696 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_004448.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250278Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135426
GnomAD4 exome AF: 0.000116 AC: 170AN: 1460494Hom.: 0 Cov.: 33 AF XY: 0.000117 AC XY: 85AN XY: 726582
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 245 of the ERBB2 protein (p.Thr245Met). This variant is present in population databases (rs376183465, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ERBB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134091). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERBB2 protein function with a negative predictive value of 80%. 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. -
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Gastric cancer;C0242379:Lung cancer;C1140680:Ovarian cancer;C2750850:Glioma susceptibility 1;C5561950:Visceral neuropathy, familial, 2, autosomal recessive Uncertain:1
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not specified Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at