Submissions for variant NM_024675.4(PALB2):c.2148T>A (p.Asn716Lys)

dbSNP: rs770145849

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236038	SCV000292650	uncertain significance	not provided	2024-01-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a neutral effect: demonstrates no impact on homology-directed repair activity in a single study (PMID: 31636395); This variant is associated with the following publications: (PMID: 31206626, 22941656, 26689913, 31636395)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000464776	SCV000550662	uncertain significance	Familial cancer of breast	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 716 of the PALB2 protein (p.Asn716Lys). This variant is present in population databases (rs770145849, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 245657). 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 not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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	RCV000574979	SCV000663345	likely benign	Hereditary cancer-predisposing syndrome	2022-04-22	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.
Color Diagnostics, LLC DBA Color Health	RCV000574979	SCV000911433	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 716 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). A functional study has been reported that this variant protein does not impact PALB2 homology-directed repair activity (PMID: 31636395). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/251492 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.
Fulgent Genetics, Fulgent Genetics	RCV002479940	SCV002776133	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-12-30	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000464776	SCV004202023	uncertain significance	Familial cancer of breast	2023-12-18	criteria provided, single submitter	clinical testing