rs45543843
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_024675.4(PALB2):c.2200A>T(p.Thr734Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000178 in 1,613,958 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. T734N) has been classified as Likely benign.
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.2200A>T | p.Thr734Ser | missense_variant | 5/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.2200A>T | p.Thr734Ser | missense_variant | 5/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000658 AC: 10AN: 152064Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251490Hom.: 0 AF XY: 0.0000662 AC XY: 9AN XY: 135918
GnomAD4 exome AF: 0.000190 AC: 278AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.000180 AC XY: 131AN XY: 727248
GnomAD4 genome ? AF: 0.0000658 AC: 10AN: 152064Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74278
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4Benign:2
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. - |
Uncertain significance, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 24, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
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]. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 16, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 17, 2023 | This missense variant replaces threonine with serine at codon 734 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 reported that this variant does not impact PALB2 function in a homology-directed repair assay (PMID: 31636395). This variant has been reported in at least 8 individuals affected with breast cancer, 1 individual affected with ovarian cancer and at least 7 individuals unaffected with breast or ovarian cancer (PMID: 17200668, 20091115, 22241545, 25186627, 26283626, 26315354, 26898890, 33471991) including two individuals age 70 years or older without cancer in the FLOSSIES database. This variant also has been reported in individuals affected with pancreatic cancer (PMID: 28767289, 32659497). This variant has been identified in 16/282876 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 | curation | Sema4, Sema4 | Mar 12, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 05, 2023 | The p.T734S variant (also known as c.2200A>T), located in coding exon 5 of the PALB2 gene, results from an A to T substitution at nucleotide position 2200. The threonine at codon 734 is replaced by serine, an amino acid with similar properties. This variant has been identified in numerous disease cohorts as well and unaffected control groups across studies (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Sauty de Chalon A et al. Breast Cancer Res. Treat. 2010 May;121:253-5; Thompson ER et al. Breast Cancer Res, 2015 Aug;17:111; Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107:; Caminsky NG et al. Hum Mutat, 2016 07;37:640-52; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lattimore V et al. Breast Cancer Res Treat, 2021 Feb;185:583-590; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In a homology-directed DNA repair (HDR) assay, this alteration was found to be functionally normal (Wiltshire T et al. Genet. Med., 2019 Oct). This amino acid position is highly 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 06, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2023 | Observed in multiple individuals with breast or pancreatic cancer (Sauty de Chalon et al., 2010; Tischkowitz et al., 2012; Tung et al., 2015; Caminsky et al., 2016; Shindo et al., 2017; Bhai et al., 2021); Observed at comparable frequencies in control populations and in individuals with breast, ovarian, or other cancers (Rahman et al., 2007; Ramus et al., 2015; Thompson et al., 2015; Decker et al., 2017; Pritchard et al., 2018; Song et al., 2020); Published functional studies suggest no damaging effect: HDR activity comparable to wild type (Wiltshire et al., 2019); 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: 26898890, 17200668, 20091115, 26283626, 25186627, 22241545, 26315354, 28779002, 28767289, 28440294, 28873162, 29641532, 32659497, 32546565, 22941656, 31636395, 34326862) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2021 | Variant summary: PALB2 c.2200A>T (p.Thr734Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 264516 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.8e-05 vs 0.00016), allowing no conclusion about variant significance. c.2200A>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rahman_2007, Sauty de Chalon_2010, , Tischkowitz_2012,Tung_2014, Thompson_2015, Ramus_2015, Caminsky_2016, Shindo_2017, and Lattimore_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported [CHEK2 c.1100delC, p.T367fs*15 (internal testing); BRCA2 c.1929delG, p.Arg645fsX15 (Tung_2014)], providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function which showed the variant to have proficient HDR activity, providing supporting evidence for a benign role (Wiltshire_2020). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Thr734Ser variant was identified in 8 of 20076 proband chromosomes (frequency: 0.0004) from individuals or families with familial breast cancer, contralateral breast cancer, male breast cancer, familial ovarian cancer, or pancreatic cancer and was present in 5 of 13026 control chromosomes (frequency: 0.0004) from healthy individuals (Rahman 2007, Thompson 2015, Tischkowitz 2012, Sauty de Chalon 2010, Tung 2015, Caminsky 2016, Ramus 2015, Shindo 2017). The variant was also identified in dbSNP (ID: rs45543843) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and 5 other submitters), LOVD 3.0 (identified by 4 submitters and curated as "effect unknown"). The variant was identified in control databases in 16 of 277228 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 14 of 126714 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr734 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Endometrial carcinoma Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Thr734Ser variant was identified in 8 of 20076 proband chromosomes (frequency: 0.0004) from individuals or families with familial breast cancer, contralateral breast cancer, male breast cancer, familial ovarian cancer, or pancreatic cancer and was present in 5 of 13026 control chromosomes (frequency: 0.0004) from healthy individuals (Rahman 2007, Thompson 2015, Tischkowitz 2012, Sauty de Chalon 2010, Tung 2015, Caminsky 2016, Ramus 2015, Shindo 2017). The variant was also identified in dbSNP (ID: rs45543843) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae and 5 other submitters), LOVD 3.0 (identified by 4 submitters and curated as "effect unknown"). The variant was identified in control databases in 16 of 277228 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24028 chromosomes (freq: 0.00004), Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 14 of 126714 chromosomes (freq: 0.0001), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr734 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at