Submissions for variant NM_024675.4(PALB2):c.3379T>C (p.Cys1127Arg)

gnomAD frequency: 0.00001  dbSNP: rs767830005

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000579960	SCV000686035	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-22	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 1127 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 28825143; DOI: 10.1101/513317 ). This variant has also been identified in 2/251436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701458	SCV000830259	uncertain significance	Familial cancer of breast	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1127 of the PALB2 protein (p.Cys1127Arg). This variant is present in population databases (rs767830005, gnomAD 0.01%). This missense change has been observed in individual(s) with PALB2-related conditions (PMID: 28825143, 36622392). ClinVar contains an entry for this variant (Variation ID: 490083). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Sema4, Sema4	RCV000579960	SCV002531174	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-24	criteria provided, single submitter	curation
Ambry Genetics	RCV000579960	SCV002616098	likely benign	Hereditary cancer-predisposing syndrome	2024-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153752	SCV003843354	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000701458	SCV005053875	uncertain significance	Familial cancer of breast	2024-02-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001030414	SCV005623230	uncertain significance	not provided	2023-10-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005019004	SCV005646456	uncertain significance	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-03-28	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030414	SCV001193403	uncertain significance	not provided	2018-08-25	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.