Submissions for variant NM_024675.4(PALB2):c.1846G>C (p.Asp616His)

gnomAD frequency: 0.00003  dbSNP: rs786201907

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164427	SCV000215066	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-16	criteria provided, single submitter	clinical testing	The p.D616H variant (also known as c.1846G>C), located in coding exon 5 of the PALB2 gene, results from a G to C substitution at nucleotide position 1846. The aspartic acid at codon 616 is replaced by histidine, 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 amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000483250	SCV000568030	uncertain significance	not provided	2022-11-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with Lynch-associated cancers and/or colon polyps and also in a patient with unilateral breast cancer; however, the variant did not segregate with breast cancer in this family (Hartley et al., 2014; Yurgelun et al., 2015; Staninova-Stojovska et al., 2019); Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wildtype (Wiltshire et al., 2020); This variant is associated with the following publications: (PMID: 25225577, 25980754, 22941656, 31942411, 31636395)
Color Diagnostics, LLC DBA Color Health	RCV000164427	SCV000690812	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 616 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). Experimental studies with the variant demonstrated no defect in a homology-directed repair assay (PMID: 31636395). This variant has been observed in two individuals with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754, 31942411) and in two individuals affected with breast cancer (PMID: 25225577, 33980423). This variant has been identified in 2/282802 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	RCV000635889	SCV000757315	uncertain significance	Familial cancer of breast	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 616 of the PALB2 protein (p.Asp616His). This variant is present in population databases (rs786201907, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer or colorectal cancer (PMID: 25225577, 28944238, 33980423). ClinVar contains an entry for this variant (Variation ID: 185069). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 31636395, 34946951). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269117	SCV001448360	uncertain significance	not specified	2020-11-25	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1846G>C (p.Asp616His) results in a non-conservative amino acid change in 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 4e-06 in 251394 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1846G>C has been reported in the literature in one individual affected with breast cancer (Hartley_2014) and individuals affected with LS-associated cancer and/or colorectal polyps (Yurgelun_2015, Staninova-Stojovska_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (Wiltshire_2019). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002492657	SCV002775794	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-10-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000635889	SCV004202080	uncertain significance	Familial cancer of breast	2023-09-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483250	SCV004222276	uncertain significance	not provided	2023-08-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with colorectal cancer (PMIDs: 31942411 (2019), 28944238 (2017)) and in an individual with a family history of breast and/or ovarian cancer (PMID: 25225577 (2014)). Additionally, a functional study suggests that the variant is not damaging to PALB2 protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.0000071 (2/282802 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.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989339	SCV004806909	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 5	2024-03-26	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000483250	SCV001193160	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.