Submissions for variant NM_024675.4(PALB2):c.814G>A (p.Glu272Lys)

gnomAD frequency: 0.00001  dbSNP: rs515726127

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165689	SCV000216427	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	The p.E272K variant (also known as c.814G>A), located in coding exon 4 of the PALB2 gene, results from a G to A substitution at nucleotide position 814. The glutamic acid at codon 272 is replaced by lysine, an amino acid with similar properties. This variant has been reported in the literature in cohorts of Finnish and Spanish breast cancer patients (Kuusisto KM et al. Breast Cancer Res. 2011 Feb;13:R20; Velázquez C et al. Breast. 2019 Feb;43:91-96). This variant was reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant was also detected in a cohort of 1280 consecutive cancer patients with breast and/or ovarian cancer (HBOC) (Butz H et al. Cancers (Basel), 2023 Aug;15). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477491	SCV000601799	uncertain significance	not provided	2024-01-26	criteria provided, single submitter	clinical testing	The PALB2 c.814G>A (p.Glu272Lys) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 21356067 (2011), 30521987 (2019), 33471991 (2021), 37686625 (2023)), and in reportedly healthy individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00012 (3/25118 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114664	SCV000633479	uncertain significance	Familial cancer of breast	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 272 of the PALB2 protein (p.Glu272Lys). This variant is present in population databases (rs515726127, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 21356067, 34284872). ClinVar contains an entry for this variant (Variation ID: 126772). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The lysine 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.
Color Diagnostics, LLC DBA Color Health	RCV000165689	SCV000908503	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 272 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast or ovarian cancer and in a breast cancer case-control meta-analysis in 3/60466 cases and 2/53461 unaffected individuals (PMID: 21356067, 30521987, 33471991; Leiden Open Variation Database DB-ID PALB2_010049). This variant has been identified in 7/282818 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.
Fulgent Genetics, Fulgent Genetics	RCV002483181	SCV002785709	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-01-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000114664	SCV004202187	uncertain significance	Familial cancer of breast	2023-06-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004595926	SCV005090211	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114664	SCV001193022	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.