chr16-23637906-A-G
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_024675.4(PALB2):c.155T>C(p.Val52Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V52I) has been classified as Likely benign.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
- Fanconi anemia complementation group NInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 3Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- familial ovarian cancerInheritance: AD Classification: MODERATE Submitted by: ClinGen
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727224 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:3Benign:1
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 52 of the PALB2 protein (p.Val52Ala). This variant is present in population databases (rs373970237, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 246458). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. -
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Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This missense variant replaces valine with alanine at codon 52 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010256) and in at least one individual unaffected with ovarian cancer (PMID: 24448499). This variant has been identified in 1/246252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
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. -
Breast neoplasm Uncertain:1
Found in a 37 year old female patient having exome sequencing for an unrelated indication. No known history of breast cancer. Family history of a mother with breast ancer diagnosed at 50, a maternal grandmother who died of breast cancer at age 58 and a paternal grandmother diagnosed with breast and ovarian cancer. -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in any cases, but was observed in an unaffected control from an ovarian cancer study (Kanchi et al., 2014); This variant is associated with the following publications: (PMID: 24448499, 20871615, 19369211) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at