Submissions for variant NM_024675.4(PALB2):c.3247G>A (p.Glu1083Lys)

gnomAD frequency: 0.00004  dbSNP: rs747785029

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196986	SCV000255099	uncertain significance	Familial cancer of breast	2023-12-26	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 1083 of the PALB2 protein (p.Glu1083Lys). This variant is present in population databases (rs747785029, gnomAD 0.003%). This missense change has been observed in individual(s) with head and neck squamous cell cancer (PMID: 26580448, 28678401). ClinVar contains an entry for this variant (Variation ID: 216753). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Counsyl	RCV000196986	SCV000488001	uncertain significance	Familial cancer of breast	2015-12-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000480697	SCV000566312	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	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; Observed in individuals with head and neck squamous cell carcinoma or neuroblastoma (Zhang et al., 2015; Chandrasekharappa et al., 2017); This variant is associated with the following publications: (PMID: 28678401, 26580448, 24485656, 20871615, 19609323)
Ambry Genetics	RCV000574156	SCV000663279	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-16	criteria provided, single submitter	clinical testing	The p.E1083K variant (also known as c.3247G>A), located in coding exon 12 of the PALB2 gene, results from a G to A substitution at nucleotide position 3247. The glutamic acid at codon 1083 is replaced by lysine, an amino acid with similar properties. This variant was reported in 0/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has also been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with a neuroblastoma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant was also been identified in a patient with a head and neck cancer (Chandrasekharappa SC et al. Cancer, 2017 Oct;123:3943-3954). This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000574156	SCV000686018	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764044	SCV000894998	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194139	SCV001363438	uncertain significance	not specified	2019-06-03	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3247G>A (p.Glu1083Lys) results in a 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3247G>A has been reported in the literature in individuals affected with head and neck squamous cell carcinoma and neuroblastoma (Chandrasekharappa_2017, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252054	SCV002523779	uncertain significance	See cases	2020-09-04	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, BP4
Myriad Genetics, Inc.	RCV000196986	SCV004019163	uncertain significance	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000196986	SCV004201995	uncertain significance	Familial cancer of breast	2023-10-29	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000574156	SCV005045348	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-02	criteria provided, single submitter	clinical testing