16-23635806-G-C
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_024675.4(PALB2):āc.740C>Gā(p.Thr247Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251278Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135876
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461870Hom.: 0 Cov.: 33 AF XY: 0.0000234 AC XY: 17AN XY: 727236
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 18, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 247 of the PALB2 protein (p.Thr247Arg). This variant is present in population databases (rs587782658, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626, 26315354). ClinVar contains an entry for this variant (Variation ID: 142706). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 23, 2017 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 19, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 26283626, 26315354, 19369211, 32546565) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2016 | Variant summary: The c.740C>G variant affects a non-conserved nucleotide, resulting in amino acid change from Thr to Arg. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is not found in 125258 control chromosomes. This variant has been detected in one BrC pt without strong evidence for causality (Thompson_BCR_2015). In addition, one clinical laboratory/reputable database classified this variant as VUS, without evidence to independently evaluate. Because of the lack of clinical information and functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2023 | This alteration is classified as likely 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at