Submissions for variant NM_024675.4(PALB2):c.2411C>T (p.Ser804Phe)

gnomAD frequency: 0.00001  dbSNP: rs149836639

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481392	SCV000565788	uncertain significance	not provided	2017-02-03	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.2411C>T at the cDNA level, p.Ser804Phe (S804F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has been observed in at least one individual with ovarian cancer (Ramus 2015). PALB2 Ser804Phe was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ser804Phe occurs at a position that is not conserved and is located in a region required for interaction with POLH and POLH DNA synthesis stimulation (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Ser804Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000581656	SCV000690845	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 804 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 reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354) and in a breast cancer case-control meta-analysis in 2/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010900). This variant has been identified in 1/251462 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635655	SCV000757076	uncertain significance	Familial cancer of breast	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 804 of the PALB2 protein (p.Ser804Phe). This variant is present in population databases (rs149836639, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 418604). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 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.
Ambry Genetics	RCV000581656	SCV002734542	likely benign	Hereditary cancer-predisposing syndrome	2024-01-15	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV002475930	SCV002789920	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-05-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000635655	SCV004202123	uncertain significance	Familial cancer of breast	2023-08-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481392	SCV004222303	uncertain significance	not provided	2022-09-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251462 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/PALB2)), epithelial ovarian cancer (PMID: 26315354 (2015)), as well as healthy controls (PMIDs: 32546565 (2021), and 33471991 (2021), See also LOVD (https://databases.lovd.nl/shared/variants/PALB2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.