Submissions for variant NM_024675.4(PALB2):c.1540G>A (p.Gly514Arg)

gnomAD frequency: 0.00001  dbSNP: rs756778249

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214985	SCV000276959	likely benign	Hereditary cancer-predisposing syndrome	2021-04-02	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.
GeneDx	RCV000589880	SCV000292647	uncertain significance	not provided	2024-03-14	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33309985, 32980694, 30287823, 33471991, 36243179)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000989570	SCV000550755	likely benign	Familial cancer of breast	2025-02-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589880	SCV000699538	uncertain significance	not provided	2016-08-08	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.1540G>A (p.Gly514Arg) variant involves the alteration of a non-conserved nucleotide. The altered amino acid Gly514 is not clocated in any known domain. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. However, this variant was found in 8/121412 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.000691 (8/11578). This frequency is about 4 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, one internal sample carries the variant of interest and a potential pathogenic APC variant (c.646-2A>G), further supporting the neutrality of the variant of interest. Taken together, this variant is classified as VUS-possibly benign.
Color Diagnostics, LLC DBA Color Health	RCV000214985	SCV000911468	likely benign	Hereditary cancer-predisposing syndrome	2021-01-06	criteria provided, single submitter	clinical testing
Mendelics	RCV000989570	SCV001140033	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001027798	SCV001190408	uncertain significance	Familial cancer of breast; Pancreatic cancer, susceptibility to, 3	2019-03-12	criteria provided, single submitter	clinical testing	PALB2 NM_024675.3 exon 4 p.Gly514Arg (c.1540G>A): This variant has not been reported in the literature and is present in 0.07% (27/34592) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-23646327-C-T). This variant amino acid Arginine (Arg) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589880	SCV001470585	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	The PALB2 c.1540G>A (p.Gly514Arg) variant has been reported in the published literature in individuals with breast cancer (PMID: 30287823 (2018), 33471991 (2021) see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)), colorectal cancer (PMID: 33309985 (2020)), biliary tract cancer (PMID: 36243179 (2022)) and pancreatic cancer (PMID: 32980694 (2020)). This variant has also been identified in unaffected individuals (PMID: 33309985 (2020), 32980694 (2020) 30287823 (2018), 36243179 (2022), 33471991 (2021) see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.00078 (27/34592 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.
Sema4, Sema4	RCV000214985	SCV002530621	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589880	SCV003799511	likely benign	not provided	2023-10-27	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000989570	SCV003843161	uncertain significance	Familial cancer of breast	2022-11-17	criteria provided, single submitter	clinical testing	The PALB2 c.1540G>A (p.Gly514Arg) missense change has a maximum subpopulation frequency of 0.078% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with breast cancer, prostate cancer, as well as in healthy controls (PMID: 30287823, 31206626, 31214711). It is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224228	SCV003920310	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-03-30	criteria provided, single submitter	clinical testing	PALB2 NM_024675.3 exon 4 p.Gly514Arg (c.1540G>A): This variant has not been reported in the literature and is present in 0.07% (27/34592) of Latino alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/16-23646327-C-T). This variant amino acid Arginine (Arg) is present in several species including multiple mammals, and it is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.