Submissions for variant NM_024675.4(PALB2):c.2509G>A (p.Glu837Lys)

gnomAD frequency: 0.00008  dbSNP: rs587778587

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656936	SCV000149996	likely benign	not provided	2020-02-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26411315, 29190888, 24728327, 24755471, 27783279, 24163242, 28796317, 29338689)
Ambry Genetics	RCV000116087	SCV000172832	likely benign	Hereditary cancer-predisposing syndrome	2021-06-15	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000989556	SCV000290839	likely benign	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000318539	SCV000396094	uncertain significance	Fanconi anemia complementation group N	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000116087	SCV000396095	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116087	SCV000902868	likely benign	Hereditary cancer-predisposing syndrome	2016-04-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121758	SCV000917952	likely benign	not specified	2020-09-04	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2509G>A (p.Glu837Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250516 control chromosomes, predominantly at a frequency of 0.0012 within the East Asian subpopulation in the gnomAD database. Specifically, the variant allele was detected at a frequency of 0.0042 within Korean controls (gnomAD) and at a frequency range of 0.0058-0.0069 within Japanese controls (Momozawa_2018 and HGVD and jMorp databases). Therefore, the observed variant frequency within East Asian control individuals is at least 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Though c.2509G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Nakagomi 2016, Kim 2017, Sato 2017, Shin_2020) and in a patient with Beckwith-Wiedemann syndrome and hepatoblastoma (Kim 2017), these patients were all of East Asian origin. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with pathogenic variants have been reported (BRCA1 c.188T>A, p.L63X; PTEN c.697C>T, p.Arg233X; Internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000989556	SCV001140004	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030647	SCV001193677	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798359	SCV002043595	uncertain significance	Breast and/or ovarian cancer	2020-05-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656936	SCV002046129	uncertain significance	not provided	2023-01-24	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0042 (16/3818 chromosomes in the Korean subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMIDs: 32019277 (2020), 30287823 (2018)) and colorectal cancer (PMIID: 33309985 (2020)). It has also been reported in a breast cancer association study where the variant was found in individuals with breast cancer as well as in unaffected controls (PMIDs: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). 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.
Genetic Services Laboratory, University of Chicago	RCV000121758	SCV002067601	uncertain significance	not specified	2018-11-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116087	SCV002530705	likely benign	Hereditary cancer-predisposing syndrome	2021-10-15	criteria provided, single submitter	curation
ITMI	RCV000121758	SCV000085956	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000116087	SCV000805277	uncertain significance	Hereditary cancer-predisposing syndrome	2018-05-01	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000121758	SCV001193239	benign	not specified	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356207	SCV001551313	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Glu837Lys variant was identified in 5 of 780 proband chromosomes (frequency: 0.0064) from individuals or families with breast cancer and was present in 1 of 124 control chromosomes (frequency: 0.008) from healthy individuals (Kim 2017, Nakagomi 2016). The variant was also identified in dbSNP (ID: rs587778587) as “With Pathogenic, other allele”, ClinVar (6x, as likely benign by Invitae, Ilummina, uncertain significance by Ambry Genetics, GeneDx, and ITMI), Clinvitae (4x), Cosmic (1x, large intestine, prostate, carcinoma), databases. The variant was not identified in MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 30 of 276582 chromosomes at a frequency of 0.000108 in the following populations: African in 6 of 25030 chromosomes (freq. 0.00024), East Asian in 24 of 18870 chromosomes (freq. 0.0013), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). A co-occurring pathogenic BRCA2 variant (c.4042delT, p.Cys1348ValfsX26) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that p.Glu837Lys variant does not have clinical significance The p.Glu837Lys residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004529947	SCV004726838	likely benign	PALB2-related disorder	2024-05-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).