Submissions for variant NM_024675.4(PALB2):c.3307G>A (p.Val1103Met)

dbSNP: rs201657283

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656941	SCV000150012	uncertain significance	not provided	2022-06-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate homology-directed repair comparable to wild-type (Wiltshire 2020); Observed in individuals with breast and other cancers as well as unaffected controls (Casadei 2011, Gonzalez-Garay 2013, Thompson 2015, Yurgelun 2015, Kim 2017, Momozawa 2018, Fujita 2020, Song 2021); This variant is associated with the following publications: (PMID: 21285249, 24082139, 26283626, 25980754, 27783279, 30287823, 32566746, 32546565, 27535533, 33309985, 31636395, 19609323, 20871615, 24485656)
Ambry Genetics	RCV000116103	SCV000185684	likely benign	Hereditary cancer-predisposing syndrome	2019-02-22	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.
Invitae	RCV000114616	SCV000255103	likely benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000114616	SCV000268025	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656941	SCV000601782	likely benign	not provided	2022-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116103	SCV000910839	likely benign	Hereditary cancer-predisposing syndrome	2015-01-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212827	SCV000917939	likely benign	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3307G>A (p.Val1103Met) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 302930 control chromosomes, predominantly at a frequency of 0.00027 within the East Asian subpopulation in the gnomAD database. Due to the underrepresentation of East Asian subpopulation in the gnomAD database, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In addition, this variant was also found at a frequency of 0.0006 in 4.7K Japanese individuals in jMorp database (healthy Japanese volunteers; PMID: 29069501). c.3307G>A has been reported in the literature in sequencing studies reporting individuals affected with Hereditary Breast And Ovarian Cancer ( example, Casadei_2011, Gonzalez-Garay_2013, Thompson_2015, Kim_2017, Momozawa_2018), individuals undergoing multigene panel testing for Lynch syndrome (example, Thompson_2015), extra hepatic bile duct cancer (example, Terashima_2019), in male and female control cohorts of unaffected Japanese individuals (example, Momozawa_2018) and recently classified as benign in a study evaluating population-based screening for hereditary colorectal cancer variants in Japan (Fujita_2020). These reports do not provide unequivocal conclusions about association of the variant with PALB2 associated Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Wiltshire_2019). These results showed no damaging effect of this variant on homology directed repair (HDR) activity of PALB2. The following publications have been ascertained in the context of this evaluation (PMID: 24082139, 25980754, 21285249, 26283626, 27783279, 30287823, 31666926, 31636395, 33309985). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=4; VUS, n=8). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000114616	SCV001139982	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030643	SCV001193673	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000116103	SCV002531166	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212827	SCV004027060	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114616	SCV001193392	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.
Genetic Services Laboratory, University of Chicago	RCV000212827	SCV003839806	uncertain significance	not specified	2022-06-27	no assertion criteria provided	clinical testing	DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.3307G>A, in exon 12 that results in an amino acid change, p.Val1103Met. This sequence change has been previously described in individuals with breast and other cancers as well as in a control population (PMID: 21285249, 27783279, 3028782 , 26283626, 33309985). Experimental studies showed no damaging effect of this variant on homology directed repair (HDR) activity of PALB2 (PMID: 31636395). This sequence change has been described in the gnomAD database with a global population frequency of 0.005% (dbSNP rs201657283). The p.Val1103Met change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1103Met substitution. Due to insufficient evidences the clinical significance of the p.Val1103Met change remains unknown at this time.