Submissions for variant NM_024675.4(PALB2):c.2135C>T (p.Ala712Val)

gnomAD frequency: 0.00017  dbSNP: rs141458731

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000417394	SCV000149989	likely benign	not specified	2017-12-12	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	RCV000116080	SCV000183791	benign	Hereditary cancer-predisposing syndrome	2015-01-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000114512	SCV000252860	benign	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114512	SCV000268008	likely benign	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Illumina Laboratory Services, Illumina	RCV000116080	SCV000396100	likely benign	Hereditary cancer-predisposing syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000405151	SCV000396101	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.
Color Diagnostics, LLC DBA Color Health	RCV000116080	SCV000685925	likely benign	Hereditary cancer-predisposing syndrome	2014-12-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000114512	SCV000785441	likely benign	Familial cancer of breast	2017-08-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759185	SCV000888364	likely benign	not provided	2023-02-20	criteria provided, single submitter	clinical testing
Mendelics	RCV000114512	SCV001140016	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116080	SCV002530672	benign	Hereditary cancer-predisposing syndrome	2020-07-07	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417394	SCV002760828	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477269	SCV002799209	likely benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-10-06	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315616	SCV004016495	benign	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114512	SCV004019620	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000759185	SCV004033463	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	PALB2: BP4
True Health Diagnostics	RCV000116080	SCV000788090	likely benign	Hereditary cancer-predisposing syndrome	2018-01-30	no assertion criteria provided	clinical testing
Leiden Open Variation Database	RCV000759185	SCV001193187	likely benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358176	SCV001553847	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Ala712Val variant was identified in 11 of 13046 proband chromosomes (frequency: 0.0008) from Jewish, Polish, German, Australian, and North American individuals or families with high-risk or familial breast, ovarian, or pancreatic cancer or Lynch syndrome and was identified in 2 of 5548 chromosomes (frequency: 0.0004) from healthy individuals (Catucci 2012, Dansonka-Mieszkowska 2010, Hellebrand 2011, Thompson 2015, Tischkowitz 2012, Yurgelun 2015, Zhen 2015). The variant was also identified in dbSNP (ID: rs141458731) “With other allele”, ClinVar (classified benign by Ambry Genetics and Invitae; and as likely benign by GeneDx and four other submitters), and LOVD 3.0 (1x). The variant was observed in control databases in 76 (1 homozygous) of 277240 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 10 of 6466 chromosomes (1 homozygous, freq: 0.002), Latino in 12 of 34420 chromosomes (freq: 0.0003), European in 36 of 126726 chromosomes (freq: 0.0003), Ashkenazi Jewish in 12 of 10152 chromosomes (freq: 0.001), and South Asian in 6 of 30782 chromosomes (freq: 0.0002); it was not observed in the African, East Asian, or Finnish populations. The variant was not identified in Cosmic, MutDB, or the Zhejiang Colon Cancer Database. The p.Ala712 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood that the variant impacts 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 this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000759185	SCV001744344	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000759185	SCV001807218	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000759185	SCV001905823	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000759185	SCV001959555	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000116080	SCV002506597	likely benign	Hereditary cancer-predisposing syndrome	2022-03-22	no assertion criteria provided	clinical testing