Submissions for variant NM_024675.4(PALB2):c.3296C>G (p.Thr1099Arg)

gnomAD frequency: 0.00003  dbSNP: rs142132127

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131652	SCV000186679	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-06	criteria provided, single submitter	clinical testing	The p.T1099R variant (also known as c.3296C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3296. The threonine at codon 1099 is replaced by arginine, an amino acid with similar properties. This alteration has previously been reported in individuals at risk for hereditary breast, ovarian, and pancreatic cancers (Tung N et al. Cancer. 2015 Jan;121(1):25-33; Ramus SJ et al. J. Natl. Cancer Inst. 2015 Aug;27;107(11); Decker B et al. J Med Genet. 2017 11;54:732-741; Abe T et al. J. Clin. Oncol. 2019 05;37(13):1070-1080; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This variant was also reported in 6/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant has been identified in the homozygous state in an individual with features consistent with Fanconi anemia (Abdulkareem AA et al. Biomed Rep, 2024 Apr;20:67). This alteration was found to be functional in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med. 2020 Mar;22(3):622-632). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000657014	SCV000292841	uncertain significance	not provided	2024-10-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast, ovarian, pancreatic, or colorectal cancer, but also in unaffected controls (PMID: 26315354, 28779002, 25186627, 31428572, 33471991, 30883245, 36627197, 35610400); This variant is associated with the following publications: (PMID: 25186627, 26315354, 26976419, 28779002, 31159747, 31422574, 30883245, 33471991, 31428572, 31636395, 24485656, 19609323, 20871615, 36627197, 35610400, 38476606, 35402282)
Counsyl	RCV000410212	SCV000488413	uncertain significance	Familial cancer of breast	2016-03-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131652	SCV000537595	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 1099 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). A functional study has shown that this variant does not affect the homology-directed DNA repair function of PALB2 protein (PMID: 31636395). This variant has been reported in individuals affected with breast cancer (PMID: 25186627, 26976419, 28779002), bladder and colorectal cancer (PMID: 30883245), and ovarian cancer (PMID: 26315354), and this variant has been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010286). This variant has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database (https://whi.color.com/variant/16-23619239-G-C), and it also has been identified in 17/282868 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410212	SCV000550779	likely benign	Familial cancer of breast	2025-02-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000235868	SCV000596218	uncertain significance	not specified	2017-06-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000657014	SCV000807106	uncertain significance	not provided	2017-11-29	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000131652	SCV000822115	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000131652	SCV000838996	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235868	SCV000919934	uncertain significance	not specified	2025-01-10	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3296C>G (p.Thr1099Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 1624922 control chromosomes, predominantly at a frequency of 0.00012 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.5e-05 vs 0.00016), allowing no conclusion about variant significance. c.3296C>G has been reported in the literature in a homozygous individual affected with Fanconi anemia, and has also been reported in the heterozygous state as a VUS in individuals affected with breast and/or ovarian cancer, as well as in individuals with colon, gastric, or bladder cancer, without strong evidence for causality (e.g. Ramus_2015, Tung_2015, Tung_2016, Abe_2019, Zhunussova_2019, Gonzalez_2022, Zhang_2023). These data indicate that the variant may be associated with disease. A co-occurrence with a pathogenic variant in another cancer-related gene has been observed (ATM c.901+1G>A, internal data). At least one publication reports experimental evidence evaluating an impact on protein function using a homology directed repair assay and showed no damaging effect of this variant on HDR function versus the WT protein (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 35610400, 31422574, 26315354, 25186627, 26976419, 31636395, 31428572, 36627197, 38476606). ClinVar contains an entry for this variant (Variation ID: 142504). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235868	SCV001134551	likely benign	not specified	2024-07-03	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001294230	SCV001483087	uncertain significance	Fanconi anemia complementation group N	2019-03-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with ovarian cancer [PMID 26315354]
Sema4, Sema4	RCV000131652	SCV002531162	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-12	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002478400	SCV002788083	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2022-03-10	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000131652	SCV002819220	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001294230	SCV003812299	uncertain significance	Fanconi anemia complementation group N	2020-03-10	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410212	SCV004019628	likely benign	Familial cancer of breast	2023-03-31	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	RCV000410212	SCV004201989	uncertain significance	Familial cancer of breast	2024-02-21	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000657014	SCV005194279	uncertain significance	not provided		criteria provided, single submitter	not provided
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000657014	SCV005877664	uncertain significance	not provided	2024-09-25	criteria provided, single submitter	clinical testing	The PALB2 c.3296C>G; p.Thr1099Arg variant (rs142132127) is reported in the literature in individuals affected with breast or ovarian cancer but also in healthy controls (Breast Cancer Association Consortium 2021, Ramus 2015, Tung 2015). Additionally, this variant has been reported in the homozygous state in an individual with features of Fanconi anemia (Abdulkareem 2024). This variant is found in the general population with an overall allele frequency of 0.006% (17/282,868 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.214). However, functional analyses suggest the variant has homology-directed repair activity similar to wildtype PALB2 (Wiltshire 2020). Due to limited and conflicting information, the clinical significance of this variant is uncertain at this time. References: Abdulkareem AA et al. Whole exome sequencing of a novel homozygous missense variant in PALB2 gene leading to Fanconi anaemia complementation group. Biomed Rep. 2024 Mar 1;20(4):67. PMID: 38476606. Breast Cancer Association Consortium et al. Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. N Engl J Med. 2021 Feb 4;384(5):428-439. PMID: 33471991. Ramus SJ et al. Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer. J Natl Cancer Inst. 2015 Aug 27;107(11):djv214. PMID: 26315354. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Wiltshire T et al. Functional characterization of 84 PALB2 variants of uncertain significance. Genet Med. 2020 Mar;22(3):622-632. PMID: 31636395.
Leiden Open Variation Database	RCV000410212	SCV001193386	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
OMIM	RCV001294230	SCV005687534	pathogenic	Fanconi anemia complementation group N	2025-01-30	no assertion criteria provided	literature only