Submissions for variant NM_024675.4(PALB2):c.3054G>C (p.Glu1018Asp)

gnomAD frequency: 0.00016  dbSNP: rs183489969

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV000114588	SCV003915563	benign	Familial cancer of breast	2023-04-05	reviewed by expert panel	curation	The c.3054G>C variant in PALB2 is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 1018 (p.Glu1018Asp). The filtering allele frequency in gnomAD v2.1.1 is 0.004 in the East Asian population, which is higher than the ClinGen HBOP threshold (>0.001) for BA1, and therefore meets this criterion. This variant has been observed in a homozygous state and phase unknown with numerous other PALB2 variants that are tentatively classified as likely pathogenic or pathogenic by the HBOP VCEP in individuals without Fanconi Anemia (GeneDx, Ambry Genetics, Invitae). This variant is functional in multiple different protein assays (PMID 31757951); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (BA1, BP2_Moderate, BP1)
Ambry Genetics	RCV000130354	SCV000185205	likely benign	Hereditary cancer-predisposing syndrome	2019-06-27	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	RCV000858970	SCV000211527	likely benign	not provided	2020-10-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28825143, 21285249, 22241545, 25575445, 26283626, 23977390, 25356972, 26489409, 26692951, 27783279, 26411315, 27616075, 28580595, 27099641, 26757417, 28664506, 31159747, 31586400, 32566746, 32426482)
Invitae	RCV000114588	SCV000253601	benign	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114588	SCV000268021	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000286032	SCV000396076	likely benign	Fanconi anemia complementation group N	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000130354	SCV000396077	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212821	SCV000699582	benign	not specified	2019-03-28	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3054G>C (p.Glu1018Asp) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 281404 control chromosomes, predominantly at a frequency of 0.0052 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3054G>C has been reported in the literature predominantly in individuals of East Asian origin affected with Hereditary Breast and Ovarian Cancer (Casadei_2011, Tischkowitz_2012, Thompson_2015, Phuah_2013, Nguyen_Dumont_2015, Kraus_2017, Li_2015, Yang_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing database (BRCA1 c.2728delC, p.Gln910fsX90), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four of these classified the variant as Benign/Likely benign and three classified it as a VUS. Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA	RCV000130354	SCV000822112	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130354	SCV000902643	benign	Hereditary cancer-predisposing syndrome	2016-04-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212821	SCV001134550	benign	not specified	2021-07-20	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030645	SCV001193675	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000858970	SCV001474440	likely benign	not provided	2019-09-04	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212821	SCV002067808	likely benign	not specified	2021-01-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130354	SCV002530749	likely benign	Hereditary cancer-predisposing syndrome	2020-12-31	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212821	SCV002551637	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000114588	SCV004175576	benign	Familial cancer of breast	2020-04-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004529923	SCV004720445	likely benign	PALB2-related disorder	2023-05-31	criteria provided, single submitter	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).
Leiden Open Variation Database	RCV000114588	SCV001193337	likely benign	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356371	SCV001551521	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Glu1018Asp variant was identified in 6 of 3322 proband chromosomes (frequency: 0.002) from individuals or families with breast or ovarian cancer (Kim 2016, Li 2015, Nakagomi 2016, Phuah 2013, Thompson 2015). The variant was also identified in the following databases: dbSNP (ID: rs183489969) as With Likely benign, Uncertain significance, other allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, CGLPMCC; classified as likely benign by Illumina; classified as Benign by Invitae), Clinvitae (conflicting interpretations of pathogenicity), Cosmic (none (score 0.69)), MutDB , LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 102 of 277208 chromosomes at a frequency of 0.000368 in the following populations: other in 3 of 6464 chromosomes (freq. 0.00046), European in 1 of 126704 chromosomes (freq. 0.000008), East Asian in 98 of 18868 chromosomes (freq. 0.005), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Glu1018 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. The variant is located with the WD40-repeat-containing domain. The variant p.Glu1018Asp was listed as a rare missense variant in a study of 155 Japanese patients with breast and/or ovarian cancers; in this family, the family history of 25 relatives was available but none were reported with breast and/or ovarian cancer (Nakagomi 2016). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.