Submissions for variant NM_024675.4(PALB2):c.2012T>G (p.Leu671Ter)

gnomAD frequency: 0.00001  dbSNP: rs755263466

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780570	SCV000917959	likely pathogenic	Familial cancer of breast	2018-08-13	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2012T>G (p.Leu671X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., p.Met723fsX21 and p.Lys974fsX5). The variant allele was found at a frequency of 8.1e-06 in 246496 control chromosomes. c.2012T>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Mannan_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002422668	SCV002722955	pathogenic	Hereditary cancer-predisposing syndrome	2022-10-12	criteria provided, single submitter	clinical testing	The p.L671* pathogenic mutation (also known as c.2012T>G), located in coding exon 5 of the PALB2 gene, results from a T to G substitution at nucleotide position 2012. This changes the amino acid from a leucine to a stop codon within coding exon 5. This alteration has been reported in multiple breast and/or ovarian cancer patients (Mannan AU et al. J Hum Genet, 2016 Jun;61:515-22; Dorling et al. N Engl J Med. 2021 02;384:428-439; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV000780570	SCV004186103	pathogenic	Familial cancer of breast	2023-09-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Baylor Genetics	RCV000780570	SCV004202684	likely pathogenic	Familial cancer of breast	2022-12-26	criteria provided, single submitter	clinical testing
Invitae	RCV000780570	SCV004297698	pathogenic	Familial cancer of breast	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu671*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is present in population databases (rs755263466, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26911350, 32885271, 33811135). ClinVar contains an entry for this variant (Variation ID: 632932). For these reasons, this variant has been classified as Pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355597	SCV001550525	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Leu671* variant was not identified in the literature nor was it identified in ClinVar, Cosmic, LOVD 3.0, or the Zhejiang University Database. The variant was identified in dbSNP (ID: rs755263466) as well as control databases in 2 of 246246 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 2 of 30782 chromosomes (freq: 0.00007), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Leu671* variant leads to a premature stop codon at position 671, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2-associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
BRCAlab, Lund University	RCV003155957	SCV002588993	pathogenic	Hereditary breast ovarian cancer syndrome	2022-08-26	no assertion criteria provided	clinical testing