Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
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. |
Gene |
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, |
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, |
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, |
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 | |
Ce |
RCV000590187 | SCV001500071 | likely benign | not provided | 2024-07-01 | criteria provided, single submitter | clinical testing | PALB2: BP1, BP4, BS3:Supporting |
CHEO Genetics Diagnostic Laboratory, |
RCV001798302 | SCV002043606 | likely benign | Breast and/or ovarian cancer | 2021-05-26 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000200990 | SCV002069441 | likely benign | not specified | 2022-01-04 | criteria provided, single submitter | clinical testing | |
National Health Laboratory Service, |
RCV002225308 | SCV002504944 | likely benign | Hereditary breast ovarian cancer syndrome | 2022-04-19 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000128994 | SCV002531196 | likely benign | Hereditary cancer-predisposing syndrome | 2021-07-01 | criteria provided, single submitter | curation | |
Myriad Genetics, |
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, |
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. |