Submissions for variant NM_024675.4(PALB2):c.1606C>T (p.Leu536=)

gnomAD frequency: 0.00193  dbSNP: rs151162255

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212798	SCV000170873	benign	not specified	2014-02-18	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	RCV000127312	SCV000213124	likely benign	Hereditary cancer-predisposing syndrome	2014-07-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Invitae	RCV001030239	SCV000252856	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212798	SCV000596214	likely benign	not specified	2017-04-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000127312	SCV000685891	likely benign	Hereditary cancer-predisposing syndrome	2015-04-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587743	SCV000699540	benign	not provided	2017-03-24	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.1606C>T (p.Leu536Leu) variant involves the alteration of a non-conserved nucleotide causing a synonymous change that 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may eliminate ESE binding sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 71/121918 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.006439 (67/10406). This frequency is about 41 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 African origin. Multiple publications have cited the variant in affected African-American individuals, although with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Taken together, this variant is classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000212798	SCV000807078	benign	not specified	2016-10-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587743	SCV000889577	benign	not provided	2022-07-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000127312	SCV002530628	benign	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498478	SCV002805905	likely benign	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-08-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492439	SCV004239550	likely benign	Breast and/or ovarian cancer	2022-10-28	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030239	SCV001193125	likely benign	Familial cancer of breast	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	RCV001355529	SCV001550445	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu536= variant was identified in 6 of 558 proband chromosomes (frequency: 0.01075) from individuals or families with breast cancer and was present in 1 of 520 control chromosomes (frequency: 0.0019) from healthy individuals (Zheng 2012,). The variant was also identified in dbSNP (ID: rs151162255) as With other allele, ClinVar (classified as benign by GeneDX, Invitae; classified as likely benign by Ambry genetics, PALB2 database), Clinvitae (classified as benign by ClinVar), Zhejiang Colon Cancer Database (2X probably does not affect function), databases. The variant was identified in control databases in 160 of 277242 chromosomes at a frequency of 0.000577 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Leu536= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000212798	SCV001807169	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000587743	SCV001951259	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000587743	SCV001977629	likely benign	not provided		no assertion criteria provided	clinical testing