Submissions for variant NM_024675.4(PALB2):c.1637T>C (p.Val546Ala)

gnomAD frequency: 0.00004  dbSNP: rs148647206

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123333	SCV000166646	uncertain significance	Familial cancer of breast	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 546 of the PALB2 protein (p.Val546Ala). This variant is present in population databases (rs148647206, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer and/or ovarian cancer (PMID: 28135145, 32546565, 34326862). ClinVar contains an entry for this variant (Variation ID: 136129). 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	RCV000215046	SCV000273481	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	The p.V546A variant (also known as c.1637T>C), located in coding exon 4 of the PALB2 gene, results from a T to C substitution at nucleotide position 1637. The valine at codon 546 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This alteration was also identified in an individual diagnosed with ovarian cancer (Song H et al. J Med Genet, 2021 May;58:305-313). 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.
GeneDx	RCV000589758	SCV000292790	uncertain significance	not provided	2024-04-30	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28779002, 28135145, 32546565, 29641532, 34326862)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589758	SCV000699541	uncertain significance	not provided	2016-03-01	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a non-conserved nucleotide and results in a replacement of a medium size and hydrophobic Valine (V) with a small size and hydrophobic Alanine (A). 2/4 in silico tools predict the variant to be benign. The variant was found in the large and broad cohorts of the ExAC project at an allele frequency of 0.0016% which does not exceed the maximal allele frequency of a disease causing PALB2 allele (0.015%). To our knowledge, the variant has not been reported in affected individuals and in vitro/vivo studies assessing the impact of the variant of the function of the protein were not published either at the time of scoring. A clinical diagnostic laboratory classifies variant as Uncertain via ClinVar (without evidence to independently evaluate). Due to the lack of clinical data and functional studies, the variant was classified as variant of uncertain significance until more information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000215046	SCV001345558	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-10	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 546 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 at least two individuals affected with breast cancer (PMID: 28779002, 30638972) and one individual each affected with ovarian cancer (PMID: 32546565) and colorectal cancer (PMID: 28135145). This variant has been identified in 6/282812 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.
Sema4, Sema4	RCV000215046	SCV002530631	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002492444	SCV002780836	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-11-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000123333	SCV004931022	benign	Familial cancer of breast	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
PreventionGenetics, part of Exact Sciences	RCV004739425	SCV005346547	uncertain significance	PALB2-related disorder	2024-03-04	no assertion criteria provided	clinical testing	The PALB2 c.1637T>C variant is predicted to result in the amino acid substitution p.Val546Ala. This variant has been reported in individuals with a history of colorectal, breast, and ovarian cancers (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145; Table S5, Decker et al. 2017. PubMed ID: 28779002; Table S3, Pritchard et al. 2018. PubMed ID: 29641532; Table S6, Song et al. 2020. PubMed ID: 32546565; Table S4, Bhai et al. 2021. PubMed ID: 34326862). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant is interpreted as uncertain by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/136129/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.