Submissions for variant NM_024675.4(PALB2):c.2014G>C (p.Glu672Gln)

gnomAD frequency: 0.02171  dbSNP: rs45532440

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV000114504	SCV003915557	benign	Familial cancer of breast	2023-04-05	reviewed by expert panel	curation	The c.2014G>C variant in PALB2 is a missense variant predicted to cause a substitution of a glutamic acid by glutamine at amino acid 672 (p.Glu672Gln). This variant has a gnomAD v2.1.1 filtering allele frequency of 0.02846 in non-Finnish European population, which is higher than the HBOP VCEP threshold (>0.001) for BA1, and therefore meets this criterion. This variant is functional in multiple protein assays (PMID: 31636395, PMID: 31757951, PMID: 33964450); however, due to a lack of known positive missense controls with known clinical impact, these 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, BP1)
Invitae	RCV000114504	SCV000153915	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000121756	SCV000170853	benign	not specified	2013-10-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000127292	SCV000212665	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Vantari Genetics	RCV000127292	SCV000267066	benign	Hereditary cancer-predisposing syndrome	2015-10-26	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114504	SCV000268006	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Color Diagnostics, LLC DBA Color Health	RCV000127292	SCV000292100	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000121756	SCV000314372	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000395482	SCV000396104	benign	Fanconi anemia complementation group N	2018-03-06	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Counsyl	RCV000114504	SCV000488426	benign	Familial cancer of breast	2016-03-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121756	SCV000539985	likely benign	not specified	2016-03-29	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 302/12994=2.3%
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000857375	SCV000604594	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225299	SCV002504930	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127292	SCV002530661	benign	Hereditary cancer-predisposing syndrome	2020-03-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121756	SCV002551670	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498480	SCV002805050	likely benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-04-26	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153363	SCV003843327	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315614	SCV004016489	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114504	SCV004044105	benign	Familial cancer of breast	2023-05-10	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
ITMI	RCV000121756	SCV000085954	not provided	not specified	2013-09-19	no assertion provided	reference population
Pathway Genomics	RCV000114504	SCV000207348	benign	Familial cancer of breast	2014-11-06	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000127292	SCV000788088	likely benign	Hereditary cancer-predisposing syndrome	2018-02-23	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000857375	SCV001193176	benign	not provided	2019-08-07	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Maximiliano Zeballos, Melissa DeRycke.
Center of Medical Genetics and Primary Health Care	RCV001269351	SCV001448698	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001269351	SCV001549473	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Glu672Gln variant was identified in 210 of 6690 proband chromosomes (frequency: 0.03) from individuals or families with breast and/or ovarian cancer (Bogdanova 2011, Rahman 2007, Teo 2013, Adank 2011, Nguyen-Dumont 2013, Kluska 2017). The variant was also identified in ClinVar (10x benign: Invitae, Ambry Genetics, Vantari Genetics, Color Genomics, Prevention Genetics, Counsyl, GeneDx, Pathway Genomics, PALB2 database; 2x likely benign: MacCallum Cancer Genetics, Illumina; 1x not provided: ITMI), MutDB (Mut Prediction score of 0.135 with link to UniProtKB/Swiss-Prot Q86YC2: Variant p.Glu672Gln which classifies this variant as a polymorphism-not reported to be implicated in disease), LOVD 3.0 (21x “does not affect function”; 3x not classified), Zhejiang University Database (5x "pathogenicity unknown"), databases. The variant was not identified in the COSMIC database. The variant was identified in control databases in 6201 of 277202 chromosomes at a frequency of 0.02 including 104 homozygous individuals increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 355 of 10152 chromosomes (freq: 0.035), European (Non-Finnish) in 3698 of 126702 chromosomes (freq: 0.029), Other in 174 of 6466 chromosomes (freq: 0.027), South Asian in 809 of 30782 chromosomes (freq: 0.026), European (Finnish) in 510 of 25782 chromosomes (freq: 0.02), Latino in 531 of 34420 chromosomes (freq: 0.015). The p.Glu672Gln residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000121756	SCV001739759	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000857375	SCV001800220	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000121756	SCV001809273	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000121756	SCV001906031	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000121756	SCV001957665	benign	not specified		no assertion criteria provided	clinical testing