Submissions for variant NM_024675.4(PALB2):c.1337A>T (p.Asp446Val)

gnomAD frequency: 0.00005  dbSNP: rs146434474

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200861	SCV000255075	uncertain significance	Familial cancer of breast	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 446 of the PALB2 protein (p.Asp446Val). This variant is present in population databases (rs146434474, gnomAD 0.03%). This missense change has been observed in individual(s) with breast cancer (PMID: 32868316). ClinVar contains an entry for this variant (Variation ID: 216742). 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.
GeneDx	RCV000255070	SCV000322092	uncertain significance	not provided	2023-04-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Purrington et al., 2020); This variant is associated with the following publications: (PMID: 22193777, 32868316, 23555315)
Ambry Genetics	RCV000562823	SCV000666855	likely benign	Hereditary cancer-predisposing syndrome	2022-02-16	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	RCV000562823	SCV000685873	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with valine at codon 446 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a woman affected with breast cancer (PMID: 32868316) and in three men (PMID: 32832836), all of whom are of African ancestry. This variant has been identified in 7/281272 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761148	SCV000891064	uncertain significance	Retinoblastoma	2017-02-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194137	SCV001363436	uncertain significance	not specified	2019-09-06	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.1337A>T (p.Asp446Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249862 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1337A>T in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255070	SCV001470583	uncertain significance	not provided	2020-07-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000562823	SCV002530607	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492922	SCV002799541	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200861	SCV004018635	likely benign	Familial cancer of breast	2023-05-05	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].
PreventionGenetics, part of Exact Sciences	RCV004530198	SCV004119068	uncertain significance	PALB2-related disorder	2022-11-18	criteria provided, single submitter	clinical testing	The PALB2 c.1337A>T variant is predicted to result in the amino acid substitution p.Asp446Val. This variant was identified in a genome-wide SNP array study of individuals with breast and prostate cancer (Table S6, Haiman et al. 2013. PubMed ID: 23555315, reported as rs146434474), a study of African-American women with breast cancer (Table S5, Purrington et al. 2020. PubMed ID: 32868316), and in a cohort of patients with advanced cancer (see eTable for Mandelker D et al 2017. PubMed ID: 28873162). No additional functional or genetic segregation data was provided in any of these studies to help establish pathogenicity of the c.1337A>T (p.Asp446Val) variant. This variant is reported in 0.029% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23646530-T-A) and has been reported in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/216742/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000200861	SCV004202007	uncertain significance	Familial cancer of breast	2024-02-20	criteria provided, single submitter	clinical testing