Submissions for variant NM_024675.4(PALB2):c.3404G>A (p.Gly1135Glu)

gnomAD frequency: 0.00005  dbSNP: rs730881894

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589198	SCV000211534	uncertain significance	not provided	2021-10-27	criteria provided, single submitter	clinical testing	Observed in individuals with rhabdosarcoma and colorecal cancer (Zhang 2015, DeRycke 2017); Published functional studies demonstrate no damaging effect: HDR activity comparable to wild type (Wiltshire 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 26580448, 28944238, 31636395, 19609323, 20871615, 24485656)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232726	SCV000290876	uncertain significance	Familial cancer of breast	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1135 of the PALB2 protein (p.Gly1135Glu). This variant is present in population databases (rs730881894, gnomAD 0.02%). This missense change has been observed in individual(s) with rhabdosarcoma or colorectal cancer (PMID: 26580448, 28944238). ClinVar contains an entry for this variant (Variation ID: 182775). 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 disruptive. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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	RCV000570480	SCV000663290	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.G1135E variant (also known as c.3404G>A), located in coding exon 13 of the PALB2 gene, results from a G to A substitution at nucleotide position 3404. The glycine at codon 1135 is replaced by glutamic acid, an amino acid with similar properties. This alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 03;22:622-632). This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with rhabdosarcoma (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). The variant has been reported in the literature in two individuals with colorectal cancer without evidence for causality (DeRycke MS. Mol Genet Genomic Med. 2017 Sep;5(5):553-569). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855602	SCV000699595	likely benign	not specified	2024-03-24	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3404G>A (p.Gly1135Glu) results in a non-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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251474 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3404G>A has been reported in the literature as a VUS in a setting of whole exome sequencing in an individual affected with rhabdosarcoma (Zhang_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been observed at our laboratory ( TP53 c.782+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example, Wiltshire_2020 summarized in Boonen_2020). These results showed no damaging effect of this variant on PALB2 function in a homology directed DNA repair (HDR) assay. The following publications have been ascertained in the context of this evaluation (PMID: 33195396, 31636395, 26580448). ClinVar contains an entry for this variant (Variation ID: 182775). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000232726	SCV000785141	uncertain significance	Familial cancer of breast	2017-05-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589198	SCV001134552	uncertain significance	not provided	2018-12-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000570480	SCV002531176	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-07	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492638	SCV002793161	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-04-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000232726	SCV004019156	likely benign	Familial cancer of breast	2023-03-30	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].
Baylor Genetics	RCV000232726	SCV004202198	uncertain significance	Familial cancer of breast	2024-03-07	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030415	SCV001193404	uncertain significance	Carcinoma of colon	2017-01-31	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Melissa DeRycke.