Submissions for variant NM_024675.4(PALB2):c.2922G>T (p.Lys974Asn)

gnomAD frequency: 0.00001  dbSNP: rs730881892

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160849	SCV000211526	uncertain significance	not provided	2021-10-19	criteria provided, single submitter	clinical testing	Observed in an individual with ovarian cancer (Ramus 2015); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20871615, 19609323, 24485656, 26315354)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205333	SCV000260980	uncertain significance	Familial cancer of breast	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 974 of the PALB2 protein (p.Lys974Asn). This variant is present in population databases (rs730881892, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 182772). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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	RCV000566246	SCV000665347	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.K974N variant (also known as c.2922G>T), located in coding exon 9 of the PALB2 gene, results from a G to T substitution at nucleotide position 2922. The lysine at codon 974 is replaced by asparagine, an amino acid with similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst. 2015 Nov;107). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566246	SCV000685992	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 974 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 26315354) and in a breast cancer case-control meta-analysis in 2/60464 cases and 2/53459 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010819). This variant has also been identified in 3/251482 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.
Counsyl	RCV000205333	SCV000786340	uncertain significance	Familial cancer of breast	2018-04-09	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000160849	SCV002010963	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267894	SCV002551643	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160849	SCV004010467	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	PALB2: BP4
Myriad Genetics, Inc.	RCV000205333	SCV004019143	uncertain significance	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000205333	SCV004202081	uncertain significance	Familial cancer of breast	2023-09-13	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355089	SCV001549864	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Lys974Asn variant was identified in 1 of 6748 proband chromosomes (frequency: 0.0002) from individuals or families with ovarian cancer and was not identified in 6974 control chromosomes from healthy individuals (Ramus 2015). The variant was also identified in dbSNP (ID: rs730881892) as “With Uncertain significance allele”, in ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics, Color Genomics), Clinvitae, and Cosmic databases. The variant was not identified in MutDB, LOVD 3.0, or Zhejiang University Database. The variant was identified in control databases in 2 of 246256 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 2 of 111706 chromosomes (freq: 0.00002), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Lys974 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.