ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3428T>A (p.Leu1143His) (rs62625284)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000585950 SCV000150013 uncertain significance not provided 2018-12-27 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3428T>A at the cDNA level, p.Leu1143His (L1143H) at the protein level, and results in the change of a Leucine to a Histidine (CTT>CAT). This variant has been observed in multiple individuals with breast, ovarian, or pancreatic cancer, but has also been observed in control subjects (Balia 2010, Catucci 2012, Catucci 2014, Kanchi 2014, Damiola 2015, Grant 2015, Lu 2015, Ramus 2015, Thompson 2015, Tung 2015, Caminsky 2016, Hauke 2018). PALB2 Leu1143His was observed at an allele frequency of 0.025% (32/126,718) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the WD6 repeat region, the region required for POLH DNA synthesis stimulation, as well as the region of interaction with RAD51, BRCA2 and POLH (Oliver 2009, Buisson 2010, Buisson 2014, UniProt). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether PALB2 Leu1143His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000114625 SCV000166662 uncertain significance Familial cancer of breast 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with histidine at codon 1143 of the PALB2 protein (p.Leu1143His). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is present in population databases (rs62625284, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with breast, ovarian and pancreatic cancer, as well as in unaffected individuals (PMID: 20852946, 22692731, 24556926, 26283626, 25186627, 25479140, 26315354, 27878467). ClinVar contains an entry for this variant (Variation ID: 126740). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000116104 SCV000186860 likely benign Hereditary cancer-predisposing syndrome 2018-12-18 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;No disease association in appropriately sized case-control study(ies)
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114625 SCV000268028 uncertain significance Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Counsyl RCV000114625 SCV000487859 uncertain significance Familial cancer of breast 2015-11-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585950 SCV000699596 uncertain significance not provided 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The PALB2 c.3428T>A (p.Leu1143His) variant involves the alteration of a conserved nucleotide and results in a replacement of a medium size and hydrophobic Leucine (L) with a medium size and polar Histidine (H) located in PALB2 WD40 domain, which is interacting with BRCA2 (PMID:21618343). 4/5 in silico tools predict a damaging outcome. This variant was found in 25/126456 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003149 (21/66678). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting the variant to be in the neutral spectrum. It was reported in several HBOC patients, however without strong evidence for pathogenicity such as co-segregation information. Another variant affecting the same codon, p.Leu1143Pro have been observed in a patient with bilateral breast cancer shown to disrupt the PALB2-RAD51C-BRCA2 complex indicating the functional importance of the Leu1143 residue (PMID:24141787, PMID:21618343). Multiple clinical diagnostic laboratories classified this variant as VUS. Taken together, this variant is classified as variant of uncertain significance until more information becomes available.
PreventionGenetics,PreventionGenetics RCV000585950 SCV000807109 uncertain significance not provided 2016-02-05 criteria provided, single submitter clinical testing
Mendelics RCV000116104 SCV000838993 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585950 SCV000888376 uncertain significance not provided 2019-02-03 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764041 SCV000894995 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000116104 SCV000902660 likely benign Hereditary cancer-predisposing syndrome 2016-05-06 criteria provided, single submitter clinical testing
Center of Medical Genetics and Primary Health Care RCV001004833 SCV000987257 uncertain significance bilateral breast cancer 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria This variant is in exon 8 of the PALB2 gene, which is involved in repairing double-strand DNA breaks in WD40 repeat-like (V872- 1185 aa) domain, which serves as platforms for the assembly of protein complexes (e.g., BRCA1 / RAD51) or mediators of transient interplay among other proteins. This variant is in a hotspot of 12 pathogenic nonsense and frameshift variants, including one mutation (i.e., c.3426dupA; p.Leu1143Thrfs) at the same position (Source ClinVar) (PM1 Pathogenic Moderate). It has been reported in several cancers including breast cancers (PMID: 27878467; 25479140; 26315354; 26283626; 21618343). Furthermore, it has been experimentally shown that this missense change modestly reduces DNA double-stranded break-induced homologous recombination, affects the PALB2 protein interaction with RAD51C, XRCC3 and BRCA2 proteins and moderately increases cellular sensitivity to ionizing radiation (PMID: 24141787). 6 pathogenic predictions from EIGEN, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT vs 5 benign predictions from DANN, DEOGEN2, MVP, PrimateAI and REVEL support its deleterious effect (PP3 Pathogenic Supporting). This variant was found in a 46-years old female with bilateral breast cancer and no reported family history of cancer. In summary, the available evidence is currently insufficient to determine the role of this variant in the disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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