Submissions for variant NM_024675.4(PALB2):c.3235G>T (p.Ala1079Ser)

gnomAD frequency: 0.00003  dbSNP: rs730881878

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160829	SCV000211502	uncertain significance	not provided	2023-03-03	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer and also in unaffected controls (Damiola et al., 2015; Decker et al., 2017; Dorling et al., 2021); Observed in a child with myeloid sarcoma, and a fibroblast sample from this patient demonstrated increased sensitivity to radiation and DNA damaging agents (Beer et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 24485656, 19609323, 20871615, 33471991, 26564480, 34382369)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543305	SCV000633414	uncertain significance	Familial cancer of breast	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1079 of the PALB2 protein (p.Ala1079Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, myelosarcoma, and/or ovarian cancer (PMID: 26564480, 32546565, 34382369). This missense change has been observed to co-occur in individuals with a different variant in PALB2 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 182756). 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. 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	RCV000564254	SCV000663280	likely benign	Hereditary cancer-predisposing syndrome	2024-10-28	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.
Color Diagnostics, LLC DBA Color Health	RCV000564254	SCV000690907	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1079 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, controlled functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26564480, 28779002) and ovarian cancer (PMID: 32546565). This variant has been observed in an infant with thoracic and intraspinal aleukaemic myeloid sarcoma, as well as in his father unaffected with cancer (PMID: 34382369). In a large breast cancer case-control study, this variant has been observed in 6/60466 cases and 1/53461 unaffected individuals with OR=5.305 (95%CI 0.639 to 44.07) and p-value=0.13 (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010612). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000543305	SCV001429035	uncertain significance	Familial cancer of breast	2018-11-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797644	SCV002041774	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3235G>T (p.Ala1079Ser) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3235G>T has been reported in the literature in individuals affected with Breast Cancer (e.g. Damiola_2015, Dorling_2021) and acute myelogenous leukaemia (Beer_2021) without evidence for causality, and also in unaffected controls (Dorling_2021). 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 have assessed the variant since 2014: all six classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160829	SCV002046317	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	The PALB2 c.3235G>T (p.Ala1079Ser) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 28779002 (2017), 26564480 (2015)), ovarian cancer (PMID: 32546565 (2021)), and myelosarcoma (PMID: 34382369 (2021)). This variant has also been observed in several breast cancer cases as well as in one control individual in a breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population, 0.000059 (4/68032 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.
Baylor Genetics	RCV000543305	SCV004202118	uncertain significance	Familial cancer of breast	2024-03-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000160829	SCV004227544	uncertain significance	not provided	2022-11-15	criteria provided, single submitter	clinical testing	BP4, PM2
Hauer Lab, Department Of Pediatric Oncology, Technical University Munich	RCV000564254	SCV001748293	likely pathogenic	Hereditary cancer-predisposing syndrome		no assertion criteria provided	research