ClinVar Miner

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

gnomAD frequency: 0.00160  dbSNP: rs139555085
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000114637 SCV000153884 benign Familial cancer of breast 2021-12-12 criteria provided, single submitter clinical testing
Ambry Genetics RCV000128994 SCV000172888 benign Hereditary cancer-predisposing syndrome 2015-06-05 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;in silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Subpopulation frequency in support of benign classification
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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000200990 SCV000601791 likely benign not specified 2017-03-30 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 2018-04-20 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
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.

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