ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3508C>T (p.His1170Tyr)

gnomAD frequency: 0.00009  dbSNP: rs200283306
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129794 SCV000184603 likely benign Hereditary cancer-predisposing syndrome 2022-09-09 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.
GeneDx RCV000212829 SCV000211537 uncertain significance not provided 2023-03-22 criteria provided, single submitter clinical testing Observed in individuals with breast or ovarian cancer and also in unaffected controls (Kanchi et al., 2014; Lu et al., 2015; Ramus et al., 2015; Myszka et al., 2017; Stafford et al., 2017; Dorling et al., 2021); Published functional studies suggest no significant impact on HDR activity (Wiltshire et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29052111, 24448499, 21618343, 26315354, 26689913, 28591191, 28873162, 23555315, 26206375, 31159747, 20871615, 19609323, 24485656, 34284872, 31636395, 33471991)
Invitae RCV000226949 SCV000290880 likely benign Familial cancer of breast 2024-01-19 criteria provided, single submitter clinical testing
Counsyl RCV000226949 SCV000487879 uncertain significance Familial cancer of breast 2015-11-24 criteria provided, single submitter clinical testing
GeneKor MSA RCV000129794 SCV000822118 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000212829 SCV000892489 likely benign not provided 2022-11-01 criteria provided, single submitter clinical testing PALB2: BP1, BP4, BS3:Supporting
Color Diagnostics, LLC DBA Color Health RCV000129794 SCV000910786 benign Hereditary cancer-predisposing syndrome 2015-11-25 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000226949 SCV001428528 uncertain significance Familial cancer of breast 2018-08-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212829 SCV001470045 uncertain significance not provided 2021-07-07 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 29522266 (2018), 29052111 (2018)), ovarian cancer (PMIDs: 28591191 (2017), 26689913 (2015), 26315354 (2015), 24448499 (2014)), and healthy individuals (PMIDs: 32658311 (2021), 32546565 (2021), 26315354 (2015), 24448499 (2014), 21618343 (2011)). Experimental studies report this variant does not affect homology directed repair, however further evidence is needed to determine the global effect of this variant on PALB2 protein activity (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.00023 (6/26134 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000212829 SCV002010956 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818304 SCV002064616 uncertain significance not specified 2021-01-04 criteria provided, single submitter clinical testing DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3508C>T, in exon 13 that results in an amino acid change, p.His1170Tyr. This sequence change does not appear to have been previously described in individuals with PALB2-related disorders and has been described in the gnomAD database with a low frequency of 0.0093% in the European sub-population (dbSNP rs200283306). The p.His1170Tyr change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.His1170Tyr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.His1170Tyr change remains unknown at this time.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001818304 SCV002500180 likely benign not specified 2023-07-05 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3508C>T (p.His1170Tyr) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251472 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PALB2 causing Breast Cancer (4.8e-05 vs 0.00016), allowing no conclusion about variant significance. c.3508C>T has been reported in the literature in individuals affected with Breast and/or ovarian cancer without evidence for causality (examples: Kanchi_2014, Ramus_2015, Stafford_2017, Myszka_2018,Tsaousis_2019, Krivokucka_2022). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one functional study reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant on homology directed repair (HDR) activity (example: Wiltshire_2019). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Fifteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=11) and benign/likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4 RCV000129794 SCV002531187 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-17 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV001818304 SCV002551622 uncertain significance not specified 2024-02-06 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000226949 SCV003843147 uncertain significance Familial cancer of breast 2022-11-04 criteria provided, single submitter clinical testing The PALB2 c.3508C>T (p.His1170Tyr) missense change has a maximum subpopulation frequency of 0.0093% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function and a functional study demonstrated that this variant does not impact homology directed repair (HDR) activity. This variant has been reported in individuals affected with breast or ovarian cancer and with suspicion of hereditary cancer predisposition (PMID: 29052111, 31159747). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc. RCV000226949 SCV004019616 likely benign Familial cancer of breast 2023-03-31 criteria provided, single submitter clinical testing This variant is considered likely 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].
Leiden Open Variation Database RCV000212829 SCV001193424 uncertain significance not provided 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.

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