chr16-23607918-G-C
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BP6
The NM_024675.4(PALB2):āc.3296C>Gā(p.Thr1099Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000353 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1099K) has been classified as Uncertain significance.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.3296C>G | p.Thr1099Arg | missense_variant | 12/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.3296C>G | p.Thr1099Arg | missense_variant | 12/13 | 1 | NM_024675.4 | P1 | |
ENST00000561764.1 | n.185+535G>C | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000636 AC: 16AN: 251484Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135918
GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28AN XY: 727224
GnomAD4 genome AF: 0.0000328 AC: 5AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74414
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:6
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 12, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Nov 15, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 24, 2023 | 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 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 24, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Familial cancer of breast Uncertain:3Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 22, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 21, 2024 | - - |
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | 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]. - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 29, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 10, 2023 | Published functional studies demonstrate no damaging effect: homology directed DNA repair activity similar to wild type (PMID: 31636395); Observed in individuals with breast, ovarian, pancreatic, or colorectal cancer, but also in unaffected controls (PMID: 26315354, 28779002, 25186627, 31428572, 33471991, 30883245); 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: 25186627, 26315354, 26976419, 28779002, 31159747, 31422574, 30883245, 19609323, 20871615, 24485656, 33471991, 31428572, 31636395) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 12, 2023 | In the published literature, this variant has been reported in individuals affected with breast cancer (PMIDs: 35402282 (2022), 26976419 (2016), 25186627 (2015)), ovarian cancer (PMID: 26315354 (2015)), and colorectal cancer (PMIDs: 31428572 (2019), 30883245 (2019)). The variant was also reported in an individual without a cancer diagnosis (PMID: 31422574 (2019)). The variant was detected in both cases and controls from a large breast cancer study (PMID: 33471991 (2021), https://databases.lovd.nl/shared/genes/PALB2). An in vivo functional study shows that the variant results in no damaging effect on protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.00029 (3/10370 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 11, 2023 | 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 6.5e-05 in 263146 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database (5 occurrences). This frequency is equal to the estimated maximal expected allele frequency of a pathogenic PALB2 variant causing Hereditary Breast and Ovarian Cancer (0.00016), suggesting this may be a benign polymorphism. c.3296C>G has been reported in the literature as a VUS in individuals affected with Breast and/or Ovarian Cancer, colon and bladder cancer (example, Ramus_2015, Tung_2015, Tung_2016, Abe_2019, Zhunussova_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (ATM c.901+1G>A), providing supporting evidence for a benign role. At least one functional study reports the result of HDR assay showed no damaging effect of this variant (Wiltshire_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 35610400, 31422574, 26315354, 25186627, 26976419, 31636395, 31428572). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=16) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 14, 2017 | - - |
Fanconi anemia complementation group N Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2019 | 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] - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 10, 2020 | - - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 10, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at