Submissions for variant NM_024675.4(PALB2):c.995T>A (p.Leu332His)

gnomAD frequency: 0.00002  dbSNP: rs377149139

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132538	SCV000187635	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-16	criteria provided, single submitter	clinical testing	The p.L332H variant (also known as c.995T>A), located in coding exon 4 of the PALB2 gene, results from a T to A substitution at nucleotide position 995. The leucine at codon 332 is replaced by histidine, an amino acid with similar properties. This alteration was detected in a patient with breast cancer and a family history of breast cancer at less than age 50 (Tung N et al. Cancer. 2015 Jan;121:25-33). This alteration was also seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 2/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). Additionally, this variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199494	SCV000255120	likely benign	Familial cancer of breast	2024-01-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000199494	SCV000488627	uncertain significance	Familial cancer of breast	2016-05-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000589127	SCV000618014	uncertain significance	not provided	2024-04-26	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 35402282, 25186627)
Color Diagnostics, LLC DBA Color Health	RCV000132538	SCV000686086	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with histidine at codon 332 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 reported for this variant. This variant has been reported in an individual affected with breast cancer at age 50 or above with low family risk (PMID: 25186627) and in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010290). This variant has been identified in 5/250756 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589127	SCV000699618	uncertain significance	not provided	2017-04-06	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.995T>A (p.Leu332His) variant located in the Partner and localiser of BRCA2, WD40 domain (via InterPro) involves the alteration of a non-conserved nucleotide and 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/121190 (1/24213), which does not exceed the estimated maximal expected allele frequency for a pathogenic PALB2 variant of 1/6397. A publication cites the variant in an affected indivdiual, although with limited information. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000199494	SCV003930442	uncertain significance	Familial cancer of breast	2023-06-14	criteria provided, single submitter	clinical testing	a variant of uncertain significance was detected in the PALB2 gene (c.995T>A).This missense variant replaces leucine with histidine at codon 332 of the PALB2 protein.ClinVar contains an entry for this variant (Variation ID: 143019) with five submitter as uncertain significant .This variant has also been identified in 5/250756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction suggests that this variant may not impact protein structure and function . This variant has been reported in individuals affected with breast cancer (PMID: 35402282, 25186627). This variant has also been identified in 5/250756 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.
Myriad Genetics, Inc.	RCV000199494	SCV004019096	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	RCV000199494	SCV004202059	uncertain significance	Familial cancer of breast	2024-03-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589127	SCV004222361	uncertain significance	not provided	2023-08-08	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 25186627 (2015), 32885271 (2021)). This variant has also been reported in unaffected cancer free individuals (PMID: 32658311 (2021), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.000035 (4/113452 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Leiden Open Variation Database	RCV000199494	SCV001193048	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354291	SCV001548870	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu332His variant was identified in 1 of 3562 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer (Tung 2015). The variant was also identified in dbSNP (ID: rs377149139) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Counsyl, Color and Integrated Genetics/Laboratory Corporation of America), and in LOVD 3.0 (1x). The variant was not identified in Cosmic, MutDB, or the Zhejiang University database. The variant was identified in control databases in 6 of 245638 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 5 of 111432 chromosomes (freq: 0.00005), and South Asian in 1 of 30658 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Leu332 residue is not conserved in mammals and four out of five 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.