16-23607883-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_024675.4(PALB2):c.3331C>G(p.Pro1111Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461746Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727180
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74310
ClinVar
Submissions by phenotype
not specified Uncertain:2
- -
Variant summary: PALB2 c.3331C>G (p.Pro1111Ala) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251456 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3331C>G has been reported in the literature in individuals affected with Breast Cancer (Dorling_2021), however, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One publication using mouse embryonic stem cells lacking Palb2 reported that complementation with the human P111A-PALB2 was able to rescue homologous recombination and confer PARPi resistance similar to levels seen with human wildtype-PALB2, with 102.61% and 87.51% relative activity, respectively (Boonen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 31757951, 33471991). Six ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Familial cancer of breast Uncertain:2
- -
This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1111 of the PALB2 protein (p.Pro1111Ala). This variant is not present in population databases (gnomAD no frequency). 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: 219647). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31757951). 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. -
Hereditary cancer-predisposing syndrome Uncertain:2
This missense variant replaces proline with alanine at codon 1111 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant has neutral impact on PALB2 function (PMID: 31757951). This variant has been reported in an individual affected with breast cancer (PMID: 29522266). This variant has not been identified 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. -
The p.P1111A variant (also known as c.3331C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3331. The proline at codon 1111 is replaced by alanine, an amino acid with highly similar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med. 2018 04;7:1349-1358). In one functional study, this variant did not significantly impair homologous recombination efficiency compared to wild-type, and was classified as a variant of uncertain significance by the authors (Boonen RACM et al. Nat Commun. 2019 11;10:5296). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1Benign:1
PALB2: BP1, BP4, BS3:Supporting -
- -
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1
- -
Hereditary breast ovarian cancer syndrome Uncertain:1
According to the ClinGen ACMG PALB2 v1.0.0 criteria we chose this criterion: BP1 (supporting benign): ClinGen: Apply to all missense variants. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at