Submissions for variant NM_024675.4(PALB2):c.400G>A (p.Asp134Asn)

gnomAD frequency: 0.00160  dbSNP: rs139555085

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000114637	SCV000153884	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000128994	SCV000172888	benign	Hereditary cancer-predisposing syndrome	2015-06-05	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.
GeneDx	RCV000590187	SCV000211544	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 31757951, 23555315, 28767289, 27878467, 25186627, 25980754, 26283626, 26979391, 21932393, 32659497)
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114637	SCV000267985	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000114637	SCV000489425	likely benign	Familial cancer of breast	2016-10-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128994	SCV000686056	likely benign	Hereditary cancer-predisposing syndrome	2015-09-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590187	SCV000699604	benign	not provided	2017-05-22	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.400G>A (p.Asp134Asn) variant involves the alteration of a non-conserved nucleotide and 5/5 in silico tools predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 54/125366 control chromosomes, predominantly observed in the African cohort at a frequency of 0.004997 (52/10406). This frequency is about 32 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. Multiple publications have cited the variant in affected individuals, however, with limited information (ie, lack of co-occurrence and/or cosegregation data). An internal LCA sample reports the variant to co-occur with a pathogenic PMS2 variant, c.2186_2187delTC (p.Leu729fs - classified as pathogenic by LCA). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely benign/benign." Taken together, this variant is classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590187	SCV000888379	benign	not provided	2022-09-05	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590187	SCV001500071	likely benign	not provided	2020-09-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798302	SCV002043606	likely benign	Breast and/or ovarian cancer	2021-05-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000200990	SCV002069441	likely benign	not specified	2022-01-04	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225308	SCV002504944	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128994	SCV002531196	likely benign	Hereditary cancer-predisposing syndrome	2021-07-01	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000114637	SCV004019619	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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Leiden Open Variation Database	RCV000114637	SCV001192975	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	RCV000590187	SCV001549815	likely benign	not provided		no assertion criteria provided	clinical testing	The PALB2 p.Asp134Asn variant was identified in 5 of 8290 proband chromosomes (frequency: 0.0006) from individuals or families with breast cancer or Lynch syndrome and was present in 1 of 4520 control chromosomes (frequency: 0.0003) from healthy individuals (Thompson 2015, Tung 2016, Yadav 2017, Yurgelun 2015, Zheng 2012). The variant was identified in dbSNP (ID: rs139555085) as “With other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Counsyl, Quest Diagnostics Nichols Institute San Juan Capistrano and Color; as uncertain significance by Cancer Genetics Laboratory/Peter MacCallum Cancer Centre; and as likely pathogenic by PALB2 database) and LOVD 3.0. The variant was also identified in control databases in 116 of 276502 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 110 of 24004 chromosomes (freq: 0.005, increasing the likelihood this could be a low frequency benign variant), Latino in 5 of 34282 chromosomes (freq: 0.0001) and European in 1 of 126534 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp134 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the Asn 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 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.